rs1048719

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.100
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
GM2ANM_000405.5 linkuse as main transcriptc.55G>A p.Ala19Thr missense_variant 1/4 ENST00000357164.4
GM2ANM_001167607.3 linkuse as main transcriptc.55G>A p.Ala19Thr missense_variant 1/4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GM2AENST00000357164.4 linkuse as main transcriptc.55G>A p.Ala19Thr missense_variant 1/41 NM_000405.5 P1
GM2AENST00000523466.5 linkuse as main transcriptc.127-6484G>A intron_variant 3

Frequencies

GnomAD3 genomes
AF:
0.0399
AC:
6070
AN:
152152
Hom.:
263
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 03, 2015- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Tay-Sachs disease, variant AB Benign:2
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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 submitterclinical testingInvitaeFeb 01, 2024- -
not provided Benign:2
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicDec 15, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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