rs117160567

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:11

Conservation

PhyloP100: -0.261

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 -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 GnomAd at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
HEXA	NM_000520.6 linkuse as main transcript	c.672+30T>G	intron_variant	ENST00000268097.10
HEXA	NM_001318825.2 linkuse as main transcript	c.705+30T>G	intron_variant
HEXA	NR_134869.3 linkuse as main transcript	n.714+30T>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.672+30T>G		intron_variant		1	NM_000520.6	P1	P06865-1
	ENST00000570175.1 linkuse as main transcript	n.2457A>C		non_coding_transcript_exon_variant	3/3	1

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

GnomAD3 exomes

AF:

0.0191

AC:

4791

AN:

250938

Hom.:

AF XY:

0.0217

AC XY:

2943

AN XY:

135610

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 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.:

AF XY:

0.0247

AC XY:

15493

AN XY:

627650

show subpopulations

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.:

Cov.:

AF XY:

0.0157

AC XY:

1172

AN XY:

74478

show subpopulations

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.:

Bravo

AF:

0.0150

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease

Pathogenic:1Benign:4

Benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	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 -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	research	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Mar 22, 2011	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	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. -

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 30, 2017	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2019	This variant is associated with the following publications: (PMID: 9150157, 28492530, 22723944, 27535533, 27884173, 7717398) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 05, 2017	- -

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

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