5-151253271-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000405.5(GM2A):c.55G>A(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,613,552 control chromosomes in the GnomAD database, including 2,409 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A19A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.040 (261 hom., cov: 32)
  • Exomes 𝑓: 0.040 (2148 hom.)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.100

Genes affected

GM2A (HGNC:4367): (ganglioside GM2 activator) This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011257827).
• BP6: Variant 5-151253271-G-A is Benign according to our data. Variant chr5-151253271-G-A is described in ClinVar as [Benign]. Clinvar id is 256030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GM2A	NM_000405.5	c.55G>A	p.Ala19Thr	missense_variant	1/4	ENST00000357164.4
GM2A	NM_001167607.3	c.55G>A	p.Ala19Thr	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GM2A	ENST00000357164.4	c.55G>A	p.Ala19Thr	missense_variant	1/4	1	NM_000405.5	P1
GM2A	ENST00000523466.5	c.127-6484G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6070 AN: 152152 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0373

GnomAD3 exomes AF: 0.0607 AC: 15228 AN: 251070 Hom.: 810 AF XY: 0.0591 AC XY: 8029 AN XY: 135744

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.197

Gnomad SAS exome AF: 0.0767

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0402 AC: 58768 AN: 1461282 Hom.: 2148 Cov.: 31 AF XY: 0.0408 AC XY: 29644 AN XY: 727032

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.112

Gnomad4 ASJ exome AF: 0.0264

Gnomad4 EAS exome AF: 0.195

Gnomad4 SAS exome AF: 0.0756

Gnomad4 FIN exome AF: 0.0410

Gnomad4 NFE exome AF: 0.0295

Gnomad4 OTH exome AF: 0.0491

GnomAD4 genome AF: 0.0398 AC: 6065 AN: 152270 Hom.: 261 Cov.: 32 AF XY: 0.0425 AC XY: 3162 AN XY: 74454

Gnomad4 AFR AF: 0.0212

Gnomad4 AMR AF: 0.0775

Gnomad4 ASJ AF: 0.0231

Gnomad4 EAS AF: 0.203

Gnomad4 SAS AF: 0.0805

Gnomad4 FIN AF: 0.0383

Gnomad4 NFE AF: 0.0292

Gnomad4 OTH AF: 0.0374

Alfa AF: 0.0331 Hom.: 323

Bravo AF: 0.0416

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.0294 AC: 253

ExAC AF: 0.0574 AC: 6971

Asia WGS AF: 0.117 AC: 408 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0288

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Tay-Sachs disease, variant AB Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	9.4
Dann	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.041
Sift	Benign	0.22	T
Sift4G	Benign	0.57	T
Polyphen		0.017	B
Vest4		0.038
MPC		0.066
ClinPred		0.0076	T
GERP RS		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.41

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: rs1048719; hg19: chr5-150632832; COSMIC: COSV64095521;