rs137902416

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012243.3(SLC35A3):c.748C>T(p.Leu250Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000144 in 1,601,026 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC35A3
NM_012243.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.88

Publications

0 publications found

Variant links:

Genes affected

SLC35A3 (HGNC:11023): (solute carrier family 35 member A3) This gene encodes a UDP-N-acetylglucosamine transporter found in the golgi apparatus membrane. In cattle, a missense mutation in this gene causes complex vertebral malformation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

SLC35A3 Gene-Disease associations (from GenCC):

autism spectrum disorder - epilepsy - arthrogryposis syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

SLC35A3 links:

ENSG00000283761 (HGNC:):

ENSG00000283761 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A3	NM_012243.3 link	c.748C>T	p.Leu250Phe	missense_variant	Exon 6 of 8	ENST00000533028.8	NP_036375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35A3	ENST00000533028.8 link	c.748C>T	p.Leu250Phe	missense_variant	Exon 6 of 8	1	NM_012243.3	ENSP00000433849.1
ENSG00000283761	ENST00000639037.1 link	c.748C>T	p.Leu250Phe	missense_variant	Exon 6 of 17	5		ENSP00000492745.1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000949

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000170

AC:

AN:

235512

AF XY:

0.0000236

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.0000332

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000915

Gnomad OTH exome

AF:

0.000175

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1449076

Hom.:

Cov.:

AF XY:

0.0000153

AC XY:

AN XY:

720426

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32712

American (AMR)

AF:

0.0000481

AC:

AN:

41562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25590

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39410

South Asian (SAS)

AF:

0.00

AC:

AN:

83078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53146

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00000993

AC:

AN:

1108028

Other (OTH)

AF:

0.0000501

AC:

AN:

59848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000329

AC:

AN:

151950

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41364

American (AMR)

AF:

0.0000656

AC:

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0000949

AC:

AN:

10538

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2086

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

Age Distribution

Genome Het

Variant carriers

<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:

0.0000581

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autism spectrum disorder - epilepsy - arthrogryposis syndrome

Uncertain:2

Nov 11, 2019

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 250 of the SLC35A3 protein (p.Leu250Phe). This variant is present in population databases (rs137902416, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SLC35A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 541610). 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 not expected to disrupt SLC35A3 protein function with a negative predictive value of 80%. 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

Uncertain

0.48

BayesDel_addAF

Benign

-0.037

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

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

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

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

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.56

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

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.3

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

PhyloP100

3.9

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.2

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

REVEL

Benign

0.25

Sift

Benign

0.079

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

Sift4G

Uncertain

0.049

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

Polyphen

0.93

.;P;P;.;.;.;P;.;.;.;.;.;.;.;.

Vest4

0.71, 0.72

MVP

0.82

ClinPred

0.90

GERP RS

4.3

Varity_R

0.53

gMVP

0.72

Mutation Taster

=50/50

(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