2-85847907-C-T

Position:

chr2-85847907-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003896.4(ST3GAL5):c.616G>A(p.Gly206Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

ST3GAL5
NM_003896.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.16

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:

ST3GAL5 (HGNC:):

ST3GAL5 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ST3GAL5	NM_003896.4 linkuse as main transcript	c.616G>A	p.Gly206Arg	missense_variant	4/7	ENST00000638572.2	NP_003887.3	Q9UNP4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ST3GAL5	ENST00000638572.2 linkuse as main transcript	c.616G>A	p.Gly206Arg	missense_variant	4/7	1	NM_003896.4	ENSP00000491316.1		Q9UNP4-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250436

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000126

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000413

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GM3 synthase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 26, 2022

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 206 of the ST3GAL5 protein (p.Gly206Arg). This variant is present in population databases (rs755430767, gnomAD 0.002%). 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: 582669). 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 disruptive. 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. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.616G>A (p.G206R) alteration is located in exon 4 (coding exon 4) of the ST3GAL5 gene. This alteration results from a G to A substitution at nucleotide position 616, causing the glycine (G) at amino acid position 206 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.53

D;.;.;.;.;.;.;.;.;.;T;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

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

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.94

D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.6

M;.;.;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-4.3

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

REVEL

Uncertain

0.48

Sift

Benign

0.069

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

Sift4G

Benign

0.090

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

Polyphen

1.0

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

Vest4

0.72, 0.73

MutPred

0.80

Gain of solvent accessibility (P = 0.0584);.;.;.;.;Gain of solvent accessibility (P = 0.0584);.;.;.;.;.;.;

MVP

0.28

MPC

1.1

ClinPred

0.98

GERP RS

5.1

Varity_R

0.44

gMVP

0.86

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