rs1800428

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000520.6(HEXA):c.9C>T(p.Ser3Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0424 in 1,613,708 control chromosomes in the GnomAD database, including 1,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 131 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1702 hom. )

Consequence

HEXA
NM_000520.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.521

Publications

15 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 links:

ENSG00000260729 (HGNC:):

ENSG00000260729 links:

HEXA-AS1 (HGNC:25810): (HEXA antisense RNA 1)

HEXA-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 15-72375964-G-A is Benign according to our data. Variant chr15-72375964-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.521 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.9C>T	p.Ser3Ser	synonymous_variant	Exon 1 of 14	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.9C>T	p.Ser3Ser	synonymous_variant	Exon 1 of 14		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.51C>T		non_coding_transcript_exon_variant	Exon 1 of 11
HEXA-AS1	NR_027262.1 link	n.-149G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.9C>T	p.Ser3Ser	synonymous_variant	Exon 1 of 14	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.9C>T		non_coding_transcript_exon_variant	Exon 1 of 16	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0329

AC:

5011

AN:

152202

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00789

Gnomad AMI

AF:

0.111

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.0510

Gnomad FIN

AF:

0.0210

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0441

Gnomad OTH

AF:

0.0320

GnomAD2 exomes

AF:

0.0415

AC:

10372

AN:

250098

AF XY:

0.0427

show subpopulations

Gnomad AFR exome

AF:

0.00791

Gnomad AMR exome

AF:

0.0269

Gnomad ASJ exome

AF:

0.0190

Gnomad EAS exome

AF:

0.113

Gnomad FIN exome

AF:

0.0231

Gnomad NFE exome

AF:

0.0431

Gnomad OTH exome

AF:

0.0395

GnomAD4 exome

AF:

0.0433

AC:

63351

AN:

1461388

Hom.:

1702

Cov.:

AF XY:

0.0438

AC XY:

31878

AN XY:

727000

show subpopulations

African (AFR)

AF:

0.00618

AC:

207

AN:

33480

American (AMR)

AF:

0.0263

AC:

1175

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0172

AC:

450

AN:

26132

East Asian (EAS)

AF:

0.139

AC:

5529

AN:

39700

South Asian (SAS)

AF:

0.0467

AC:

4024

AN:

86256

European-Finnish (FIN)

AF:

0.0241

AC:

1277

AN:

52972

Middle Eastern (MID)

AF:

0.0409

AC:

235

AN:

5740

European-Non Finnish (NFE)

AF:

0.0432

AC:

48067

AN:

1111996

Other (OTH)

AF:

0.0395

AC:

2387

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3852

7704

11557

15409

19261

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1820

3640

5460

7280

9100

<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:

0.0329

AC:

5007

AN:

152320

Hom.:

131

Cov.:

AF XY:

0.0325

AC XY:

2420

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00786

AC:

327

AN:

41590

American (AMR)

AF:

0.0251

AC:

385

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3470

East Asian (EAS)

AF:

0.114

AC:

590

AN:

5164

South Asian (SAS)

AF:

0.0508

AC:

245

AN:

4824

European-Finnish (FIN)

AF:

0.0210

AC:

223

AN:

10624

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0441

AC:

2999

AN:

68018

Other (OTH)

AF:

0.0317

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

248

496

743

991

1239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

192

256

320

<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:

0.0381

Hom.:

Bravo

AF:

0.0317

Asia WGS

AF:

0.0680

AC:

236

AN:

3478

EpiCase

AF:

0.0433

EpiControl

AF:

0.0453

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Aug 01, 2012

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 15, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Tay-Sachs disease

Benign:4

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Jul 19, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

0.52

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=296/4

polymorphism (auto)

(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