rs1048723

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr5-151267451-A-G
• chr5-151267451-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000405.5(GM2A):​c.582A>G​(p.Ter194Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,613,664 control chromosomes in the GnomAD database, including 63,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5159 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58440 hom.)
• Consequence: GM2A NM_000405.5 stop_retained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.644
• Publications: 19 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, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-151267451-A-G is Benign according to our data. Variant chr5-151267451-A-G is described in ClinVar as Benign. ClinVar VariationId is 167152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.644 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000405.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	NM_000405.5	MANE Select	c.582A>G	p.Ter194Ter	stop_retained	Exon 4 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.413-41A>G		intron	N/A	NP_001161079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	ENST00000357164.4	TSL:1 MANE Select	c.582A>G	p.Ter194Ter	stop_retained	Exon 4 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000937902.1		c.420A>G	p.Ter140Ter	stop_retained	Exon 3 of 3	ENSP00000607961.1
	GM2A	ENST00000523004.1	TSL:1	c.*526A>G		downstream_gene	N/A	ENSP00000430541.1	H0YBY3

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37477 AN: 152004 Hom.: 5153 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.303 AC: 75980 AN: 251122 AF XY: 0.300

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.277 AC: 404436 AN: 1461542 Hom.: 58440 Cov.: 37 AF XY: 0.278 AC XY: 202236 AN XY: 727086

African (AFR) AF: 0.132 AC: 4414 AN: 33480

American (AMR) AF: 0.495 AC: 22145 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8759 AN: 26134

East Asian (EAS) AF: 0.278 AC: 11017 AN: 39696

South Asian (SAS) AF: 0.329 AC: 28411 AN: 86242

European-Finnish (FIN) AF: 0.247 AC: 13194 AN: 53404

Middle Eastern (MID) AF: 0.333 AC: 1921 AN: 5766

European-Non Finnish (NFE) AF: 0.268 AC: 297909 AN: 1111730

Other (OTH) AF: 0.276 AC: 16666 AN: 60390

GnomAD4 genome AF: 0.246 AC: 37496 AN: 152122 Hom.: 5159 Cov.: 32 AF XY: 0.251 AC XY: 18648 AN XY: 74374

African (AFR) AF: 0.132 AC: 5489 AN: 41512

American (AMR) AF: 0.390 AC: 5966 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1140 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1428 AN: 5170

South Asian (SAS) AF: 0.339 AC: 1633 AN: 4824

European-Finnish (FIN) AF: 0.239 AC: 2533 AN: 10586

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

European-Non Finnish (NFE) AF: 0.271 AC: 18444 AN: 67964

Other (OTH) AF: 0.278 AC: 587 AN: 2112

Alfa AF: 0.275 Hom.: 5309

Bravo AF: 0.255

Asia WGS AF: 0.269 AC: 933 AN: 3478

EpiCase AF: 0.281

EpiControl AF: 0.287

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Tay-Sachs disease, variant AB (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.6
DANN	Benign	0.58
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1048723; hg19: chr5-150647012; COSMIC: COSV64095746; COSMIC: COSV64095746;