ENST00000523004.1:c.*294A>C

Variant names:

• chr5-151267219-A-C
• rs2075783
• ENST00000523004.1:c.*294A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000523004.1(GM2A):​c.*294A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,589,246 control chromosomes in the GnomAD database, including 62,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4856 hom., cov: 32)
  • Exomes 𝑓: 0.28 (57217 hom.)
• Consequence: GM2A ENST00000523004.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13
• Publications: 15 publications found

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]

GM2A Gene-Disease associations (from GenCC):

• Tay-Sachs disease AB variant

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 5-151267219-A-C is Benign according to our data. Variant chr5-151267219-A-C is described in ClinVar as Benign. ClinVar VariationId is 1234926.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.377 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000523004.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	NM_000405.5	MANE Select	c.427-77A>C		intron	N/A	NP_000396.2
	GM2A	NM_001167607.3		c.413-273A>C		intron	N/A	NP_001161079.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	ENST00000523004.1	TSL:1	c.*294A>C		3_prime_UTR	Exon 2 of 2	ENSP00000430541.1
	GM2A	ENST00000357164.4	TSL:1 MANE Select	c.427-77A>C		intron	N/A	ENSP00000349687.3

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34317 AN: 152084 Hom.: 4849 Cov.: 32

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.328

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.240

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.264

GnomAD4 exome AF: 0.276 AC: 396094 AN: 1437044 Hom.: 57217 Cov.: 29 AF XY: 0.277 AC XY: 198415 AN XY: 715446

African (AFR) AF: 0.0550 AC: 1809 AN: 32914

American (AMR) AF: 0.492 AC: 21418 AN: 43558

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 8658 AN: 25884

East Asian (EAS) AF: 0.278 AC: 10892 AN: 39190

South Asian (SAS) AF: 0.330 AC: 28012 AN: 84920

European-Finnish (FIN) AF: 0.247 AC: 13024 AN: 52692

Middle Eastern (MID) AF: 0.332 AC: 1899 AN: 5722

European-Non Finnish (NFE) AF: 0.269 AC: 294142 AN: 1092672

Other (OTH) AF: 0.273 AC: 16240 AN: 59492

GnomAD4 genome AF: 0.226 AC: 34330 AN: 152202 Hom.: 4856 Cov.: 32 AF XY: 0.230 AC XY: 17143 AN XY: 74398

African (AFR) AF: 0.0582 AC: 2420 AN: 41550

American (AMR) AF: 0.385 AC: 5890 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.328 AC: 1137 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1430 AN: 5174

South Asian (SAS) AF: 0.339 AC: 1632 AN: 4818

European-Finnish (FIN) AF: 0.240 AC: 2539 AN: 10594

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18449 AN: 67988

Other (OTH) AF: 0.264 AC: 557 AN: 2112

Alfa AF: 0.258 Hom.: 2818

Bravo AF: 0.231

Asia WGS AF: 0.265 AC: 919 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.7
DANN	Benign	0.38
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2075783; hg19: chr5-150646780; COSMIC: COSV64095441; COSMIC: COSV64095441;