Menu
GeneBe

rs764343937

chr15-72353179-C-Achr15-72353179-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong

The NM_000520.6(HEXA):c.460-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,570,824 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 (★★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_acceptor

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.81
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 16 ACMG points.

PVS1
?
    PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.06918239 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.3, offset of -45, new splice context is: atctccctgtgcccccatAGtaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
    PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
    PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 15-72353179-C-A is Pathogenic according to our data. Variant chr15-72353179-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HEXANM_000520.6 linkuse as main transcriptc.460-1G>T splice_acceptor_variant ENST00000268097.10
HEXANM_001318825.2 linkuse as main transcriptc.493-1G>T splice_acceptor_variant
HEXANR_134869.3 linkuse as main transcriptn.502-1G>T splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HEXAENST00000268097.10 linkuse as main transcriptc.460-1G>T splice_acceptor_variant 1 NM_000520.6 P1P06865-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000460
AC:
7
AN:
152144
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
248284
Hom.:
0
AF XY:
0.0000149
AC XY:
2
AN XY:
134136
show subpopulations
Gnomad AFR exome
AF:
0.000187
Gnomad AMR exome
AF:
0.0000292
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000423
AC:
6
AN:
1418680
Hom.:
0
Cov.:
25
AF XY:
0.00000424
AC XY:
3
AN XY:
708332
show subpopulations
Gnomad4 AFR exome
AF:
0.000153
Gnomad4 AMR exome
AF:
0.0000225
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000460
AC:
7
AN:
152144
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.000169
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000166
Hom.:
0
Bravo
AF:
0.0000416
ExAC
?
    Exome Aggregation Consortium database
AF:
0.0000247
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tay-Sachs disease Pathogenic:5Other:1
Affects, no assertion criteria providedliterature onlyOMIMJun 01, 1991- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Mar 17, 2017- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJun 03, 2016Variant summary: The HEXA c.460-1G>T variant involves the alteration of a conserved intronic nucleotide at the splice acceptor site of intron 4. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict that this variant abolishes the 3' splicing acceptor site. This variant has been found in two patients with Tay-Sachs disease in homozygous and heterozygous state, repectively. HEX A activity in these patients was extremely low or absent. This variant was also found in 3/96942 control chromosomes at a frequency of 0.0000309, which does not exceed the estimated maximal expected allele frequency of a pathogenic HEXA variant (0.0013975). In addition, OMIM and HGMD report this variant as pathogenic/disease variant. Taken together, this variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Nov 08, 2021NM_000520.4(HEXA):c.460-1G>T is a canonical splice variant classified as likely pathogenic in the context of hexosaminidase A deficiency. c.460-1G>T has been observed in cases with relevant disease (PMID: 1827945, 31388111). Functional assessments of this variant are not available in the literature. c.460-1G>T has been observed in population frequency databases (gnomAD: AFR 0.02%). In summary, NM_000520.4(HEXA):c.460-1G>T is a canonical splice variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 15, 2023This sequence change affects an acceptor splice site in intron 4 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 (rs764343937, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with Tay-Sachs disease (PMID: 1827945). ClinVar contains an entry for this variant (Variation ID: 496011). 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. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityNov 11, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.41
Cadd
Pathogenic
31
Dann
Uncertain
1.0
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
1.0
D
MutationTaster
Benign
1.0
D;D;D;D;D
GERP RS
5.4

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.92
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.92
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: rs764343937; hg19: chr15-72645520; API