rs771732955

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_003896.4(ST3GAL5):c.601G>A(p.Gly201Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,034 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 Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

ST3GAL5
NM_003896.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.16

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

GM3 synthase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ST3GAL5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_003896.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.986

PP5

Variant 2-85847922-C-T is Pathogenic according to our data. Variant chr2-85847922-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 254246.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST3GAL5	NM_003896.4 link	c.601G>A	p.Gly201Arg	missense_variant	Exon 4 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.601G>A	p.Gly201Arg	missense_variant	Exon 4 of 7	1	NM_003896.4	ENSP00000491316.1		Q9UNP4-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

250756

AF XY:

0.00000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000540

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

GM3 synthase deficiency

Pathogenic:2

Dec 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 201 of the ST3GAL5 protein (p.Gly201Arg). This variant is present in population databases (rs771732955, gnomAD 0.003%). This missense change has been observed in individual(s) with reduced gangliosides in serum but atypical clinical features for GM3 synthase deficiency (PMID: 27232954). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 254246). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ST3GAL5 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Sep 16, 2016

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.70

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

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.99

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

MetaSVM

Uncertain

-0.17

MutationAssessor

Pathogenic

3.6

H;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

7.2

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.4

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

REVEL

Pathogenic

0.67

Sift

Uncertain

0.017

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.99, 0.99

MutPred

0.93

Gain of MoRF binding (P = 0.0082);.;.;.;.;Gain of MoRF binding (P = 0.0082);.;.;.;.;.;.;

MVP

0.12

MPC

1.1

ClinPred

1.0

GERP RS

5.1

Varity_R

0.82

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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rs771732955

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over