2-85861188-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003896.4(ST3GAL5):c.311A>G(p.His104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 1,594,414 control chromosomes in the GnomAD database, including 35,802 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H104L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.18 ( 2910 hom., cov: 31)

Exomes 𝑓: 0.21 ( 32892 hom. )

Consequence

ST3GAL5
NM_003896.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.10

Publications

27 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035613477).

BP6

Variant 2-85861188-T-C is Benign according to our data. Variant chr2-85861188-T-C is described in ClinVar as Benign. ClinVar VariationId is 130382.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ST3GAL5	NM_003896.4 link	c.311A>G	p.His104Arg	missense_variant	Exon 3 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.311A>G	p.His104Arg	missense_variant	Exon 3 of 7	1	NM_003896.4	ENSP00000491316.1		Q9UNP4-1

Frequencies

GnomAD3 genomes

AF:

0.179

AC:

27292

AN:

152132

Hom.:

2913

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0771

Gnomad AMI

AF:

0.204

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.152

Gnomad EAS

AF:

0.310

Gnomad SAS

AF:

0.344

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.189

GnomAD2 exomes

AF:

0.217

AC:

54473

AN:

251086

AF XY:

0.226

show subpopulations

Gnomad AFR exome

AF:

0.0726

Gnomad AMR exome

AF:

0.148

Gnomad ASJ exome

AF:

0.154

Gnomad EAS exome

AF:

0.321

Gnomad FIN exome

AF:

0.252

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.209

AC:

301568

AN:

1442164

Hom.:

32892

Cov.:

AF XY:

0.213

AC XY:

152873

AN XY:

718782

show subpopulations

African (AFR)

AF:

0.0707

AC:

2344

AN:

33170

American (AMR)

AF:

0.150

AC:

6701

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.151

AC:

3934

AN:

26020

East Asian (EAS)

AF:

0.271

AC:

10706

AN:

39548

South Asian (SAS)

AF:

0.315

AC:

26980

AN:

85738

European-Finnish (FIN)

AF:

0.256

AC:

13639

AN:

53254

Middle Eastern (MID)

AF:

0.166

AC:

887

AN:

5328

European-Non Finnish (NFE)

AF:

0.205

AC:

224531

AN:

1094646

Other (OTH)

AF:

0.198

AC:

11846

AN:

59758

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

10821

21642

32462

43283

54104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7626

15252

22878

30504

38130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.179

AC:

27280

AN:

152250

Hom.:

2910

Cov.:

AF XY:

0.184

AC XY:

13729

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.0769

AC:

3197

AN:

41566

American (AMR)

AF:

0.166

AC:

2542

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.152

AC:

526

AN:

3470

East Asian (EAS)

AF:

0.309

AC:

1601

AN:

5184

South Asian (SAS)

AF:

0.343

AC:

1652

AN:

4816

European-Finnish (FIN)

AF:

0.242

AC:

2566

AN:

10588

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.214

AC:

14564

AN:

68004

Other (OTH)

AF:

0.190

AC:

401

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1117

2234

3351

4468

5585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

304

608

912

1216

1520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.197

Hom.:

13073

Bravo

AF:

0.165

TwinsUK

AF:

0.205

AC:

760

ALSPAC

AF:

0.214

AC:

826

ESP6500AA

AF:

0.0758

AC:

334

ESP6500EA

AF:

0.198

AC:

1705

ExAC

AF:

0.222

AC:

26999

Asia WGS

AF:

0.262

AC:

909

AN:

3478

EpiCase

AF:

0.203

EpiControl

AF:

0.209

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GM3 synthase deficiency

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 21, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Aug 27, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.23

DEOGEN2

Benign

0.17

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

Eigen

Benign

-0.97

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.40

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

MetaRNN

Benign

0.0036

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.4

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

PhyloP100

1.1

PrimateAI

Benign

0.36

PROVEAN

Benign

0.10

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

REVEL

Benign

0.082

Sift

Benign

1.0

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

Sift4G

Benign

0.69

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

Polyphen

0.0

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

Vest4

0.033, 0.018, 0.017

MPC

0.37

ClinPred

0.000012

GERP RS

5.0

Varity_R

0.039

gMVP

0.54

Mutation Taster

=98/2

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over