rs1800430

Positions:

chr15-72346662-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000520.6(HEXA):c.1195A>G(p.Asn399Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00732 in 1,614,028 control chromosomes in the GnomAD database, including 451 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N399I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.031 ( 213 hom., cov: 30)

Exomes 𝑓: 0.0048 ( 238 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.18

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000520.6

BP4

Computational evidence support a benign effect (MetaRNN=0.0056626797).

BP6

Variant 15-72346662-T-C is Benign according to our data. Variant chr15-72346662-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 93188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
HEXA	NM_000520.6 linkuse as main transcript	c.1195A>G	p.Asn399Asp	missense_variant	11/14	ENST00000268097.10
HEXA	NM_001318825.2 linkuse as main transcript	c.1228A>G	p.Asn410Asp	missense_variant	11/14
HEXA	NR_134869.3 linkuse as main transcript	n.1116-337A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10 linkuse as main transcript	c.1195A>G	p.Asn399Asp	missense_variant	11/14	1	NM_000520.6	P1	P06865-1
	ENST00000570175.1 linkuse as main transcript	n.1442T>C		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes

AF:

0.0311

AC:

4734

AN:

152114

Hom.:

213

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00207

Gnomad OTH

AF:

0.0264

GnomAD3 exomes

AF:

0.00909

AC:

2287

AN:

251478

Hom.:

101

AF XY:

0.00711

AC XY:

966

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.00847

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.00199

Gnomad OTH exome

AF:

0.00587

GnomAD4 exome

AF:

0.00484

AC:

7075

AN:

1461796

Hom.:

238

Cov.:

AF XY:

0.00442

AC XY:

3214

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.107

Gnomad4 AMR exome

AF:

0.00906

Gnomad4 ASJ exome

AF:

0.00115

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000823

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00215

Gnomad4 OTH exome

AF:

0.00881

GnomAD4 genome

AF:

0.0311

AC:

4737

AN:

152232

Hom.:

213

Cov.:

AF XY:

0.0302

AC XY:

2251

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.105

Gnomad4 AMR

AF:

0.0123

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00207

Gnomad4 OTH

AF:

0.0261

Alfa

AF:

0.00738

Hom.:

Bravo

AF:

0.0353

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.103

AC:

453

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.0110

AC:

1331

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.00164

EpiControl

AF:

0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 04, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 24, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 17, 2022	- -

Tay-Sachs disease

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 25, 2017	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 25, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.34

CADD

Benign

3.8

DANN

Benign

0.60

DEOGEN2

Uncertain

0.72

D;.;D

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.38

T;T;T

MetaRNN

Benign

0.0057

T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.14

N;.;.

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.87

N;N;N

REVEL

Benign

0.27

Sift

Benign

0.47

T;T;T

Sift4G

Benign

0.38

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.20

MPC

0.21

ClinPred

0.0017

GERP RS

-12

Varity_R

0.068

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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