15-72345454-T-C

Position:

• chr15-72345454-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000520.6(HEXA):​c.1518A>G​(p.Glu506=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.979 in 1,614,144 control chromosomes in the GnomAD database, including 778,550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.89 (62364 hom., cov: 34)
  • Exomes 𝑓: 0.99 (716186 hom.)
• Consequence: HEXA NM_000520.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.293

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 15-72345454-T-C is Benign according to our data. Variant chr15-72345454-T-C is described in ClinVar as [Benign]. Clinvar id is 93191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72345454-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.293 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.1518A>G	p.Glu506=	synonymous_variant	13/14	ENST00000268097.10
HEXA	NM_001318825.2	c.1551A>G	p.Glu517=	synonymous_variant	13/14
HEXA	NR_134869.3	n.1303A>G		non_coding_transcript_exon_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.1518A>G	p.Glu506=	synonymous_variant	13/14	1	NM_000520.6	P1
	ENST00000570175.1	n.234T>C		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes AF: 0.889 AC: 135239 AN: 152172 Hom.: 62345 Cov.: 34

Gnomad AFR AF: 0.613

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.962

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.921

GnomAD3 exomes AF: 0.971 AC: 244012 AN: 251424 Hom.: 119593 AF XY: 0.979 AC XY: 133012 AN XY: 135894

Gnomad AFR exome AF: 0.605

Gnomad AMR exome AF: 0.981

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 0.999

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.988

GnomAD4 exome AF: 0.988 AC: 1444272 AN: 1461854 Hom.: 716186 Cov.: 51 AF XY: 0.989 AC XY: 719550 AN XY: 727228

Gnomad4 AFR exome AF: 0.600

Gnomad4 AMR exome AF: 0.979

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 0.998

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.975

GnomAD4 genome AF: 0.889 AC: 135312 AN: 152290 Hom.: 62364 Cov.: 34 AF XY: 0.892 AC XY: 66419 AN XY: 74474

Gnomad4 AFR AF: 0.613

Gnomad4 AMR AF: 0.962

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 0.997

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.922

Alfa AF: 0.961 Hom.: 59319

Bravo AF: 0.873

Asia WGS AF: 0.977 AC: 3397 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.997

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 18, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Tay-Sachs disease Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 04, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 29, 2017	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 18, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs4777502; hg19: chr15-72637795;