rs200926928

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000520.6(HEXA):c.986+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000291 in 1,612,988 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 0.000027 ( 0 hom. )

Consequence

HEXA
NM_000520.6 splice_region, intron

Scores

Splicing: ADA: 0.9996

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 5.95

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]

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-72349076-T-C is Pathogenic according to our data. Variant chr15-72349076-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.986+3A>G	splice_region_variant, intron_variant	Intron 8 of 13	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1019+3A>G	splice_region_variant, intron_variant	Intron 8 of 13		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1028+3A>G	splice_region_variant, intron_variant	Intron 8 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.986+3A>G		splice_region_variant, intron_variant	Intron 8 of 13	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.413-2751A>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251270

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135818

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1460678

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726738

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000481

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000264

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:7

Aug 21, 2014

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Sep 08, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The HEXA c.986+3A>G splice region variant has been reported in at least four studies in which it is found in a total of three patients in a compound heterozygous state and in a heterozygous state in one obligate carrier (Richard et al. 1995; Akerman et al. 1997; Giraud et al. 2010; Saunders et al. 2012). One compound heterozygote presented with the late-infantile onset form of Tay-Sachs disease while another compound heterozygote had onset in adulthood. Control data are unavailable for this variant which is reported at a frequency of 0.000025 in the total population from the Exome Aggregation Consortium. In one study, exons 7 to 9 of the c.986+3A>G variant HEXA were amplified and the resulting mRNA product was shown to be lacking exon 8, suggesting this variant affects splicing (Richard et al. 1995). Based on the evidence, the c.986+3A>G variant is classified as likely pathogenic for hexoaminidase A deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 13, 2016

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 16, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 8 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs200926928, gnomAD 0.01%). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 7551830, 23035047, 24518553). 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: 188929). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 8, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7551830). For these reasons, this variant has been classified as Pathogenic. -

Apr 09, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HEXA c.986+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. A publication, Richard_1995, functionally assessed the variant and found it to cause exon 8 to be deleted, which is located in the Glycoside hydrolase family 20, catalytic domain (via InterPro). The variant was observed with an allele frequency of 8.1e-06 in 246182 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (8.1e-06 vs 0.0014), allowing no conclusion about variant significance. The variant, c.986+3A>G, has been reported in the literature in individuals affected with Tay-Sachs Disease. These data indicate that the variant is likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 12, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1019+3A>G variant in HEXA (also reported as c.986+3A>G in the literature) has been reported in the compound heterozygous state in at least 3 individuals with Tay-Sachs disease and in the heterozygous state in 1 individual where a second HEXA allele was not identified (Richard 1995 PMID: 7551830, Giraud 2010 PMID: 20100466, Saunders 2012 PMID: 23035047, Jamali 2014 PMID: 24518553). This variant has also been reported in by other clinical laboratories in ClinVar (Variation ID: 188929) and been identified in 0.007% (5/68032) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is located in the 3' splice region. Computational tools predict a splicing impact, and functional studies confirm skipping of exon 8 leading to a premature stop codon which is predicted to result in an abnormal or absent protein (Richard 1995 PMID: 7551830). Biallelic loss of function of the HEXA gene is an established disease mechanism in autosomal recessive Tay-Sachs disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Tay-Sachs disease. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting. -

HEXA-related disorder

Pathogenic:1

Mar 06, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HEXA c.986+3A>G variant is predicted to interfere with splicing. This variant has been reported in individuals with Tay-Sachs disease (Richard et al. 1995. PubMed ID: 7551830; Table 2, Akerman et al. 1997. PubMed ID: 9150157; Table 1, Giraud et al. 2010. PubMed ID: 20100466; Saunders et al. 2012. PubMed ID: 23035047). Splicing assays also reveal this variant results in exclusion of exon 8 (Richard et al. 1995. PubMed ID: 7551830). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Apr 18, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the variant a damaging effect on splicing of HEXA mRNA (Richard et al., 1995); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31980526, 9150157, 24518553, 20100466, 29790872, 7551830, 23035047) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.59

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.39

Position offset: 1

DS_DL_spliceai

0.59

Position offset: 3

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over