rs141952252

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_012243.3(SLC35A3):c.886A>G(p.Ser296Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000264 in 1,550,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S296N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

SLC35A3
NM_012243.3 missense, splice_region

Scores

Splicing: ADA: 0.9976

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 6.14

Publications

2 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: Pathogenic. The variant received 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 1-100017814-A-G is Pathogenic according to our data. Variant chr1-100017814-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 89030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A3	NM_012243.3 link	c.886A>G	p.Ser296Gly	missense_variant, splice_region_variant	Exon 7 of 8	ENST00000533028.8	NP_036375.1	Q9Y2D2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35A3	ENST00000533028.8 link	c.886A>G	p.Ser296Gly	missense_variant, splice_region_variant	Exon 7 of 8	1	NM_012243.3	ENSP00000433849.1		Q9Y2D2-1
ENSG00000283761	ENST00000639037.1 link	c.753+2394A>G		intron_variant	Intron 6 of 16	5		ENSP00000492745.1		A0A1W2PSA9

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00202

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:

0.0000617

AC:

AN:

210628

AF XY:

0.0000607

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000201

GnomAD4 exome

AF:

0.0000236

AC:

AN:

1398718

Hom.:

Cov.:

AF XY:

0.0000215

AC XY:

AN XY:

696176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29830

American (AMR)

AF:

0.00

AC:

AN:

32070

Ashkenazi Jewish (ASJ)

AF:

0.00101

AC:

AN:

24870

East Asian (EAS)

AF:

0.00

AC:

AN:

37054

South Asian (SAS)

AF:

0.00

AC:

AN:

75608

European-Finnish (FIN)

AF:

0.0000378

AC:

AN:

52944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4908

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1083696

Other (OTH)

AF:

0.0000173

AC:

AN:

57738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.0000526

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.000209

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autism spectrum disorder - epilepsy - arthrogryposis syndrome

Pathogenic:5

Jan 21, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: c.1226A>G affects a conserved nucleotide, resulting in amino acid change from Asn to Ser. 2/3 in-silico tools predict this variant to be pathogenic. 3/3 in silico tools via Alamut predict loss of RNA splicing acceptor site and ESEFinder predicts gain of binding motifs for splicing enhancers. The variant was detected a a low frequency in the large and broad ExAC cohort (0.007%). This variant has been reported in 8 affected pts from a pedigree of families that are descendents of two separate couples. In this large pedigree, there is clear co-segregation of the variant with disease. (Edvardson_2013). A functional study showed this variant resulted in exon skipping and no functional SLC35A3 protein produced (Edvardson_ 2013). Taken together, this variant was classified as a Pathogenic. -

Nov 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 296 of the SLC35A3 protein (p.Ser296Gly). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs141952252, gnomAD 0.1%). This missense change has been observed in individual(s) with autism spectrum disorder, epilepsy and arthrogryposis (PMID: 24031089). 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: 89030). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. Studies have shown that this missense change results in skipping of exon 7 and introduces a new termination codon (PMID: 24031089). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Sep 22, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Oct 01, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate that this variant results in skipping of exon 8 and is predicted to cause frame shift at the protein level, leading to an unstable, non-functional SLC35A3 protein (Edvardson S et al., 2013); Variant predicted to result in protein truncation, as the variant is predicted to result in the skipping of a portion of exon 8 resulting in a frameshift, and other loss-of-function variants have been reported; This variant is associated with the following publications: (PMID: 24031089) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.017

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.40

T;T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.077

T;T;T

PhyloP100

6.1

ClinPred

0.44

GERP RS

5.2

Varity_R

0.32

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.43

Position offset: 1

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