Genetic Variant NM_003896.4:c.831G>A (chr2-85846395-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003896.4(ST3GAL5):c.831G>A(p.Met277Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

ST3GAL5
NM_003896.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.63

Variant links:

Genes affected

ST3GAL5 (HGNC:10872): (ST3 beta-galactoside alpha-2,3-sialyltransferase 5) Ganglioside GM3 is known to participate in the induction of cell differentiation, modulation of cell proliferation, maintenance of fibroblast morphology, signal transduction, and integrin-mediated cell adhesion. The protein encoded by this gene is a type II membrane protein which catalyzes the formation of GM3 using lactosylceramide as the substrate. The encoded protein is a member of glycosyltransferase family 29 and may be localized to the Golgi apparatus. Mutation in this gene has been associated with Amish infantile epilepsy syndrome. Transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ST3GAL5 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20425737).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST3GAL5	NM_003896.4 link	c.831G>A	p.Met277Ile	missense_variant	Exon 5 of 7	ENST00000638572.2	NP_003887.3	Q9UNP4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ST3GAL5	ENST00000638572.2 link	c.831G>A	p.Met277Ile	missense_variant	Exon 5 of 7	1	NM_003896.4	ENSP00000491316.1		Q9UNP4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

GM3 synthase deficiency

Uncertain:1

Apr 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 277 of the ST3GAL5 protein (p.Met277Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ST3GAL5-related conditions. ClinVar contains an entry for this variant (Variation ID: 566048). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.79

DEOGEN2

Benign

0.19

T;.;.;.;.;.;.;.;.;.;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.076

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;.;.;D;D;D;.;.;.;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.20

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.27

.;N;N;.;.;.;.;.;.;.;.;.

REVEL

Benign

0.071

Sift

Benign

0.65

.;T;T;.;.;.;.;.;.;.;.;.

Sift4G

Benign

0.82

.;T;T;.;.;.;.;.;.;.;.;.

Polyphen

0.16

B;B;B;B;.;.;.;B;B;B;.;B

Vest4

0.32, 0.32

MutPred

0.68

Loss of catalytic residue at M277 (P = 0.0167);.;.;.;.;Loss of catalytic residue at M277 (P = 0.0167);.;.;.;.;.;.;

MVP

0.061

MPC

0.35

ClinPred

0.78

GERP RS

4.8

Varity_R

0.31

gMVP

0.89

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over