rs117160567

Variant names:

• chr15-72351103-A-C
• rs117160567
• NM_000520.6:c.672+30T>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000520.6(HEXA):​c.672+30T>G variant causes a intron 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: HEXA NM_000520.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:12
• Conservation: PhyloP100: -0.261

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]

ENSG00000261460 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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. Variant chr15-72351103-A-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.672+30T>G		intron_variant	Intron 6 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.705+30T>G		intron_variant	Intron 6 of 13		NP_001305754.1
HEXA	NR_134869.3	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	c.672+30T>G		intron_variant	Intron 6 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.412+4456T>G		intron_variant	Intron 3 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2433 AN: 152172 Hom.: 39 Cov.: 32

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

GnomAD3 exomes AF: 0.0191 AC: 4791 AN: 250938 Hom.: 87 AF XY: 0.0217 AC XY: 2943 AN XY: 135610

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 SAS exome AF: 0.0457

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.: 18 AF XY: 0.0247 AC XY: 15493 AN XY: 627650

Gnomad4 AFR exome AF: 0.00415

Gnomad4 AMR exome AF: 0.00743

Gnomad4 ASJ exome AF: 0.0201

Gnomad4 EAS exome AF: 0.000155

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.00930

Gnomad4 NFE exome AF: 0.0251

Gnomad4 OTH exome AF: 0.0201

GnomAD4 genome AF: 0.0160 AC: 2435 AN: 152290 Hom.: 40 Cov.: 32 AF XY: 0.0157 AC XY: 1172 AN XY: 74478

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.0115

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0494

Gnomad4 FIN AF: 0.00706

Gnomad4 NFE AF: 0.0240

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0219 Hom.: 42

Bravo AF: 0.0150

Asia WGS AF: 0.0260 AC: 92 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Pathogenic:1 Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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. -

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

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 -

not specified Benign:4

-

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. -

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 -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 05, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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) -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.2
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs117160567; hg19: chr15-72643444;