rs121907977

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_000520.6(HEXA):c.902T>G(p.Met301Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M301L) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:1

Conservation

PhyloP100: 9.21

Publications

6 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 15-72349163-A-C is Pathogenic according to our data. Variant chr15-72349163-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3933.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.902T>G	p.Met301Arg	missense_variant	Exon 8 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.935T>G	p.Met312Arg	missense_variant	Exon 8 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.944T>G		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.902T>G	p.Met301Arg	missense_variant	Exon 8 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.413-2838T>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152258

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251438

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000123

AC:

AN:

1461500

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000186

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111650

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41458

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.000207

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68054

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:3Uncertain:1Other:1

Mar 30, 2022

MGZ Medical Genetics Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 1993

OMIM

Significance:Affects

Review Status:no assertion criteria provided

Collection Method:literature only

- -

May 03, 2023

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.902T>G (p.Met301Arg) results in a non-conservative amino acid change located in the Glycoside hydrolase family 20, catalytic domain (IPR015883) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251438 control chromosomes. c.902T>G has been reported in the literature in homozygous and compound heterozygous individuals affected with Tay-Sachs Disease (Akil_1993, Cheema_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 8490625, 33083013). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Pathogenic (n=1), Likely Pathogenic (n=1) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Aug 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 3933). This missense change has been observed in individual(s) with Tay-Sachs disease (PMID: 8490625, 33083013). This variant is present in population databases (rs121907977, gnomAD 0.01%). This sequence change replaces methionine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 301 of the HEXA protein (p.Met301Arg). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HEXA protein function. For these reasons, this variant has been classified as Pathogenic. -

Feb 21, 2020

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variation in exon 8 of the HEXA gene that results in the amino acid substitution of Arginine for Methionine at codon 301 was detected. The observed variant c.902T>G (p.Met301Arg) has not been reported in the 1000 genomes and ExAC databases. The in silico prediction of the variant is possibly damaging by PolyPhen-2 (HumDiv) and damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -

Tay-Sachs disease;C0268275:Tay-Sachs disease, variant AB

Pathogenic:1

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.55

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.97

D;.;D

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

M;.;.

PhyloP100

9.2

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-4.9

D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

0.97

D;.;.

Vest4

0.97

MutPred

0.91

Gain of catalytic residue at M301 (P = 0.0631);.;Gain of catalytic residue at M301 (P = 0.0631);

MVP

0.99

MPC

0.93

ClinPred

0.97

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.99

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over