NM_000520.6:c.972T>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_000520.6(HEXA):c.972T>A(p.Val324Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

HEXA
NM_000520.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: -0.912

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

Tay-Sachs disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

HEXA links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 15-72349093-A-T is Pathogenic according to our data. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943. Variant chr15-72349093-A-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 3943.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.972T>A	p.Val324Val	synonymous_variant	Exon 8 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.1005T>A	p.Val335Val	synonymous_variant	Exon 8 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.1014T>A		non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.972T>A	p.Val324Val	synonymous_variant	Exon 8 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.413-2768T>A		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:1Uncertain:1

Apr 14, 2025

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: HEXA c.972T>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site in exon 8 located 17 base pairs upstream of the canonical intron 8 splice donor site. The variant was absent in 251352 control chromosomes. c.972T>A has been reported in the literature in at-least one compound heterozygous individual affected with GM2-gangliosidosis (example: Wicklow_2004). At least one publication reports experimental evidence that this variant affects mRNA splicing. Specifically, bioinformatics prediction of utilization of the alternate donor site was confirmed using cDNA from this affected individual and consisted of both normal and short transcript (example: Wicklow_2004). Authors state that RT/PCR analyses confirmed the presence of low levels of abnormal transcript in proband fibroblasts that contained a premature stop codon in the mRNA at a position equivalent to amino acid 340, and therefore rapid decay of the transcript via NMD. Sequencing of this abnormal transcript revealed a 17 base pair deletion due to the usage of the novel upstream splice donor site in exon 8. The following publication has been ascertained in the context of this evaluation (PMID: 15108204). ClinVar contains an entry for this variant (Variation ID: 3943). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mar 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 3943). This variant has been observed in individual(s) with hexosaminidase A deficiency (PMID: 15108204). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 324 of the HEXA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXA protein. -

Gm2-gangliosidosis, subacute

Pathogenic:1

Jun 01, 2004

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Apr 01, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and in silico splice prediction algorithms suggest a damaging effect resulting in aberrant splicing (Wicklow et al., 2004); This variant is associated with the following publications: (PMID: 35936646, 15108204) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

-0.91

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.89

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.89

Position offset: 3

DS_DL_spliceai

0.25

Position offset: -14

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over