chr15-72348047-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000520.6(HEXA):โ€‹c.1073+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000604 in 1,602,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (โ˜…โ˜…).

Frequency

Genomes: ๐‘“ 0.00022 ( 0 hom., cov: 32)
Exomes ๐‘“: 0.00064 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21O:2

Conservation

PhyloP100: 7.34
Variant links:
Genes affected
HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.054716982 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.4, offset of 17, new splice context is: aggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 15-72348047-C-T is Pathogenic according to our data. Variant chr15-72348047-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72348047-C-T is described in Lovd as [Pathogenic]. Variant chr15-72348047-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEXANM_000520.6 linkc.1073+1G>A splice_donor_variant, intron_variant Intron 9 of 13 ENST00000268097.10 NP_000511.2 P06865-1A0A0S2Z3W3
HEXANM_001318825.2 linkc.1106+1G>A splice_donor_variant, intron_variant Intron 9 of 13 NP_001305754.1 P06865H3BP20B4DVA7
HEXANR_134869.3 linkn.1115+1G>A splice_donor_variant, intron_variant Intron 9 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEXAENST00000268097.10 linkc.1073+1G>A splice_donor_variant, intron_variant Intron 9 of 13 1 NM_000520.6 ENSP00000268097.6 P06865-1
ENSG00000260729ENST00000379915.4 linkn.413-1722G>A intron_variant Intron 3 of 15 2 ENSP00000478716.1 A0A087WUJ7

Frequencies

GnomAD3 genomes
AF:
0.000223
AC:
34
AN:
152156
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000219
AC:
55
AN:
251210
Hom.:
0
AF XY:
0.000206
AC XY:
28
AN XY:
135768
show subpopulations
Gnomad AFR exome
AF:
0.0000617
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000431
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000644
AC:
934
AN:
1450438
Hom.:
0
Cov.:
29
AF XY:
0.000605
AC XY:
437
AN XY:
722324
show subpopulations
Gnomad4 AFR exome
AF:
0.0000602
Gnomad4 AMR exome
AF:
0.0000895
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.000817
Gnomad4 OTH exome
AF:
0.000433
GnomAD4 genome
AF:
0.000223
AC:
34
AN:
152274
Hom.:
0
Cov.:
32
AF XY:
0.000201
AC XY:
15
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.0000962
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000385
Hom.:
0
Bravo
AF:
0.000283
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000465
AC:
4
ExAC
AF:
0.000222
AC:
27
EpiCase
AF:
0.000327
EpiControl
AF:
0.000178

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:21Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tay-Sachs disease Pathogenic:13Other:1
Dec 23, 2021
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 17, 2014
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Jun 01, 1993
OMIM
Significance: Affects
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Nov 12, 2019
Myriad Genetics, Inc.
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

NM_000520.4(HEXA):c.1073+1G>A(aka IVS9+1G>A) is classified as pathogenic in the context of hexosaminidase A deficiency. Please note that the c.1073+1G>A variant is associated with Tay-Sachs disease. Sources cited for classification include the following: PMID 8444467, 1387685, 22789865, 17015493, 8490625, 1837283 and 1301938. Classification of NM_000520.4(HEXA):c.1073+1G>A(aka IVS9+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -

Mar 25, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 20, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects a donor splice site in intron 9 of the HEXA gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in HEXA are known to be pathogenic (PMID: 1833974, 8490625). This variant is present in population databases (rs76173977, gnomAD 0.04%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1387685, 8490625, 19858779, 33426165). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 3920). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Apr 10, 2014
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Oct 26, 2021
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Nov 14, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The HEXA c.1073+1G>A variant involves the alteration of a highly conserved nucleotide in the canonical splice donor site in intron 9. This variant was found in 27/119996 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0003776 (25/66208). This frequency is about lower the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). This variant is a known common pathogenic variant mainly found in non-Jewish Caucasian (Landels_1992, Landels_1993, McDowell_1992, Akli_1993, Gort_2012, Utz_2015) with consistent genotype-phenotype and functional data. The frequency in control population therefore represents the carrier frequency. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic. -

Feb 02, 2022
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Tay-Sachs disease (MIM#272800). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. RT-PCR analysis on patient fibroblasts showed this variant has multiple aberrant splicing outcomes (PMID: 1301938). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (57 heterozygotes, 0 homozygotes). (SP) 0703 - Other splice site variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. Two other canonical splice site variants, c.1073+1G>C and c.1073+1G>T, have been reported in ClinVar as pathogenic and likely pathogenic respectively. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in individuals with Tay-Sachs disease (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 30, 2015
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant has been previously reported as disease-causing and was found twice in our laboratory in trans with another pathogenic variant: in a 25-year-old female [with c.820-7G>A] with motor delay, hypotonia, scoliosis, progressive weakness, mild ankle contractures, mildly diminished sensation, gait abnormalities, sister possibly similarly symptomatic (not tested); in a 1-year-old male [with Y427fs] with IUGR, severe delays with regression, hypotonia, epilepsy, microcephaly, FTT, polymicrogyria, absent HEXA activity. Variant pathogenic in recessive state; heterozygotes are carriers. -

Aug 22, 2018
Illumina Laboratory Services, Illumina
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HEXA c.1073+1G>A variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The c.1073+1G>A variant affects a splice donor site in intron 9 and has been primarily reported in non-Ashkenazi Jewish probands of European descent (Park et al. 2010). Across a selection of available literature, the c.1073+1G>A variant has been identified in a homozygous state in three probands, in a compound heterozygous state in eight probands, in a heterozygous state in five probands in whom a second variant was not identified, and in seven probands in whom zygosity is unknown (Landels et al. 1992; McDowell et al. 1992; Akli et al. 1992; Akerman et al. 1992; Landels et al. 1993; Gort et al. 2012). The c.1073+1G>A variant was also identified in a heterozygous state in 25 unaffected carriers. The c.1073+1G>A variant was absent from 56 control alleles and is reported at a frequency of 0.000388 in the European (non-Finnish) population of the Genome Aggregation Database. RT-PCR analysis demonstrated that the c.1073+1G>A variant disrupts splicing of the HEXA gene and results in the production of numerous abnormal mRNA products (Akerman et al. 1992). Based on the evidence, the c.1073+1G>A variant is classified as pathogenic for hexoaminidase A deficiency. -

Dec 29, 2021
Revvity Omics, Revvity
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 17, 2017
Natera, Inc.
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Pathogenic:6Other:1
Oct 01, 2022
CeGaT Center for Human Genetics Tuebingen
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

HEXA: PVS1, PM2, PM3 -

Jun 12, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The HEXA c.1073+1G>A variant disrupts a canonical splice-donor site and interferes with normal HEXA mRNA splicing (PMIDs: 1301938 (1992), 1387685 (1992)). In the published literature, this variant has been reported in individuals/families affected with the classic, infantile form of Tay-Sachs disease (also known as GM2 gangliosidosis) (PMIDs: 1307230 (1992), 8444467 (1993)) and with a late-onset form of the disease (LOTS) (PMIDs: 31076878 (2019), 33426165 (2021)). The frequency of this variant in the general population, 0.00059 (30/50744 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jan 20, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Identified on approximately 17% of alleles from non-Jewish Caucasians with Tay-Sachs disease and is associated with infantile onset (Akerman et al., 1992); Canonical splice site variant predicted to result in an in-frame deletion of exon 9; Published functional studies demonstrate c.1073+1 G>A destroys the canonical splice donor site in intron 9, activates a cryptic donor site, and causes abnormal gene splicing (Akerman et al., 1992; Akli et al., 1993); This variant is associated with the following publications: (PMID: 22344438, 25525159, 22975760, 28476546, 29152458, 1837283, 29930972, 21228398, 8444467, 26874567, 29352662, 26633545, 1387685, 1301938, 17237499, 31076878, 31980526, 33426165, 25900722, 8326491) -

Nov 08, 2012
Eurofins Ntd Llc (ga)
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
MutSpliceDB: a database of splice sites variants effects on splicing, NIH
Significance: not provided
Review Status: no classification provided
Collection Method: research

- -

Oct 23, 2020
Institute of Medical Genetics and Applied Genomics, University Hospital Tรผbingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 27, 2024
Mayo Clinic Laboratories, Mayo Clinic
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP1_strong, PM2_moderate, PM3_very_strong, PVS1_moderate -

HEXA-related disorder Pathogenic:1
Jun 19, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The HEXA c.1073+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also described as IVS9+1G>A, has been documented as causative for Tay-Sachs disease (Akli et al. 1991. PubMed ID: 1837283; Park et al. 2010. PubMed ID: 19858779). This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases Pathogenic:1
Nov 06, 2017
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1073+1G>A intronic pathogenic mutation (also known as IVS9+1G>A) results from a G to A substitution one nucleotide after coding exon 9 of the HEXA gene. This mutation is one of the most common found outside the Ashkenazi Jewish population, resulting in the activation of a cryptic donor site and abnormal RNA with a 17-bp insertion, which in turn leads to a reading frame shift and premature truncation (Akli S et al. Hum Genet. 1993;90(6):614-620). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
34
DANN
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.95
SpliceAI score (max)
0.93
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.53
Position offset: -16
DS_DL_spliceai
0.93
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs76173977; hg19: chr15-72640388; COSMIC: COSV51505747; COSMIC: COSV51505747; API