NM_000405.5:c.582A>T

Variant names:

• chr5-151267451-A-T
• rs1048723
• NM_000405.5:c.582A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PM4

The NM_000405.5(GM2A):​c.582A>T​(p.Ter194Tyrext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. *194*) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GM2A NM_000405.5 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.644

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000405.5 Downstream stopcodon found after 203 codons.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GM2A	NM_000405.5	c.582A>T	p.Ter194Tyrext*?	stop_lost	Exon 4 of 4	ENST00000357164.4	NP_000396.2
GM2A	NM_001167607.3	c.413-41A>T		intron_variant	Intron 3 of 3		NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GM2A	ENST00000357164.4	c.582A>T	p.Ter194Tyrext*?	stop_lost	Exon 4 of 4	1	NM_000405.5	ENSP00000349687.3
GM2A	ENST00000523004.1	c.*526A>T		downstream_gene_variant		1		ENSP00000430541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.49
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.13	N
PhyloP100		0.64
Vest4		0.011
GERP RS		-2.1
Mutation Taster		=103/97	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs1048723; hg19: chr5-150647012;