rs1800428

chr15-72375964-G-A

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.9C>T(p.Ser3=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.521

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 93193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72375964-G-A is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
HEXA	NM_000520.6	c.9C>T	p.Ser3=	synonymous_variant	1/14	ENST00000268097.10
HEXA	NM_001318825.2	c.9C>T	p.Ser3=	synonymous_variant	1/14
HEXA	NR_134869.3	n.51C>T		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.9C>T	p.Ser3=	synonymous_variant	1/14	1	NM_000520.6	P1

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5011 AN: 152202 Hom.: 132 Cov.: 32

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

GnomAD3 exomes AF: 0.0415 AC: 10372 AN: 250098 Hom.: 289 AF XY: 0.0427 AC XY: 5777 AN XY: 135386

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 SAS exome AF: 0.0472

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.: 31 AF XY: 0.0438 AC XY: 31878 AN XY: 727000

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0263

Gnomad4 ASJ exome AF: 0.0172

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.0467

Gnomad4 FIN exome AF: 0.0241

Gnomad4 NFE exome AF: 0.0432

Gnomad4 OTH exome AF: 0.0395

GnomAD4 genome AF: 0.0329 AC: 5007 AN: 152320 Hom.: 131 Cov.: 32 AF XY: 0.0325 AC XY: 2420 AN XY: 74482

Gnomad4 AFR AF: 0.00786

Gnomad4 AMR AF: 0.0251

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.114

Gnomad4 SAS AF: 0.0508

Gnomad4 FIN AF: 0.0210

Gnomad4 NFE AF: 0.0441

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.0382 Hom.: 74

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:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2015	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Tay-Sachs disease Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 19, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	10
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

LitVar

Other links and lift over

dbSNP: rs1800428; hg19: chr15-72668305; COSMIC: COSV51505476; COSMIC: COSV51505476;