rs117160567

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000570175.1(ENSG00000261460):n.2457A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0227 in 1,390,626 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 40 hom., cov: 32)

Exomes 𝑓: 0.024 ( 438 hom. )

Consequence

ENSG00000261460
ENST00000570175.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12

Conservation

PhyloP100: -0.261

Publications

5 publications found

Variant links:

Genes affected

ENSG00000261460 (HGNC:58304):

ENSG00000261460 links:

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 15-72351103-A-C is Benign according to our data. Variant chr15-72351103-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 256351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.016 (2435/152290) while in subpopulation SAS AF = 0.0494 (238/4822). AF 95% confidence interval is 0.0442. There are 40 homozygotes in GnomAd4. There are 1172 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6 link	c.672+30T>G	intron_variant	Intron 6 of 13	ENST00000268097.10	NP_000511.2	P06865-1A0A0S2Z3W3
HEXA	NM_001318825.2 link	c.705+30T>G	intron_variant	Intron 6 of 13		NP_001305754.1	P06865H3BP20B4DVA7
HEXA	NR_134869.3 link	n.714+30T>G	intron_variant	Intron 6 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10 link	c.672+30T>G		intron_variant	Intron 6 of 13	1	NM_000520.6	ENSP00000268097.6		P06865-1
ENSG00000260729	ENST00000379915.4 link	n.412+4456T>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1		A0A087WUJ7

Frequencies

GnomAD3 genomes

AF:

0.0160

AC:

2433

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00478

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.0190

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.0489

Gnomad FIN

AF:

0.00706

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.0191

AC:

4791

AN:

250938

AF XY:

0.0217

show subpopulations

Gnomad AFR exome

AF:

0.00438

Gnomad AMR exome

AF:

0.00692

Gnomad ASJ exome

AF:

0.0191

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.00814

Gnomad NFE exome

AF:

0.0231

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0236

AC:

29195

AN:

1238336

Hom.:

438

Cov.:

AF XY:

0.0247

AC XY:

15493

AN XY:

627650

show subpopulations

African (AFR)

AF:

0.00415

AC:

120

AN:

28942

American (AMR)

AF:

0.00743

AC:

330

AN:

44438

Ashkenazi Jewish (ASJ)

AF:

0.0201

AC:

497

AN:

24782

East Asian (EAS)

AF:

0.000155

AC:

AN:

38716

South Asian (SAS)

AF:

0.0467

AC:

3815

AN:

81700

European-Finnish (FIN)

AF:

0.00930

AC:

496

AN:

53320

Middle Eastern (MID)

AF:

0.0197

AC:

106

AN:

5382

European-Non Finnish (NFE)

AF:

0.0251

AC:

22759

AN:

908026

Other (OTH)

AF:

0.0201

AC:

1066

AN:

53030

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1605

3211

4816

6422

8027

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0160

AC:

2435

AN:

152290

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1172

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00476

AC:

198

AN:

41568

American (AMR)

AF:

0.0115

AC:

176

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0190

AC:

AN:

3472

East Asian (EAS)

AF:

0.000579

AC:

AN:

5178

South Asian (SAS)

AF:

0.0494

AC:

238

AN:

4822

European-Finnish (FIN)

AF:

0.00706

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0240

AC:

1633

AN:

68020

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

121

241

362

482

603

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0206

Hom.:

103

Bravo

AF:

0.0150

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:1Benign:4

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

South Asian population allele frequency is 4.368% (rs117160567, 1395/30540 alleles, 49 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.3.2, this variant is classified as BENIGN. Following criteria are met: BA1 -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

The c.672+30T>G variant in HEXA has been identified in at least 1 Tay-Sachs disease carrier (PMID: 7717398), and has been identified in >4% of South Asian chromosomes and 43 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for Tay-Sachs disease. -

Mar 22, 2011

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

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

not specified

Benign:4

Dec 30, 2017

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

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: frequency. OB 12/23/15: 4.6% freq in South Asian chr -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HEXA c.705+30T>G variant was not identified in the ClinVar, Cosmic, MutDB or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs117160567) and in control databases in 5209 of 282340 chromosomes (93 homozygous) at a frequency of 0.018449 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1395 of 30540 chromosomes (freq: 0.04568), European (non-Finnish) in 2954 of 128924 chromosomes (freq: 0.02291), Ashkenazi Jewish in 197 of 10352 chromosomes (freq: 0.01903), Other in 114 of 7212 chromosomes (freq: 0.01581), European (Finnish) in 194 of 25090 chromosomes (freq: 0.007732), Latino in 246 of 35372 chromosomes (freq: 0.006955), African in 105 of 24924 chromosomes (freq: 0.004213) and East Asian in 4 of 19926 chromosomes (freq: 0.000201). This variant was identified in an unaffected carrier with another disease-causing mutation for Tay-Sachs disease, suggesting that this variant is not associated with disease (Triggs-Rainer_1995_PMID:7717398). The c.705+30T>G variant occurs outside the splicing consensus sequence and is not predicted to have an impact on splicing by 4 of 4 in silico splicing softwares (SpliceSiteFinder-Like, MaxEntScan, NNSplice, GeneSplicer). In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

not provided

Benign:4

Apr 19, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 9150157, 28492530, 22723944, 27535533, 27884173, 7717398) -

Apr 05, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

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

-0.84

CADD

Benign

1.2

(source)

DANN

Benign

0.77

PhyloP100

-0.26

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs117160567

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