X-48904809-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_005660.3(SLC35A2):c.1100A>G(p.Gln367Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,209,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q367K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Consequence

SLC35A2
NM_005660.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.567

Variant links:

Genes affected

SLC35A2 (HGNC:11022): (solute carrier family 35 member A2) This gene encodes a member of the nucleotide-sugar transporter family. The encoded protein is a multi-pass membrane protein. It transports UDP-galactose from the cytosol into Golgi vesicles, where it serves as a glycosyl donor for the generation of glycans. Mutations in this gene cause congenital disorder of glycosylation type IIm (CDG2M). Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Oct 2014]

SLC35A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.092608035).

BP6

Variant X-48904809-T-C is Benign according to our data. Variant chrX-48904809-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1449924.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A2	NM_005660.3 link	c.1100A>G	p.Gln367Arg	missense_variant	Exon 4 of 5	ENST00000247138.11	NP_005651.1	P78381-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35A2	ENST00000247138.11 link	c.1100A>G	p.Gln367Arg	missense_variant	Exon 4 of 5	1	NM_005660.3	ENSP00000247138.5		P78381-1

Frequencies

GnomAD3 genomes

AF:

0.0000357

AC:

AN:

111966

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000130

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

181488

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000154

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000455

AC:

AN:

1097696

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363064

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

AC:

AN:

26399

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35180

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19368

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

30200

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

54044

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40455

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

841848

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

46072

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000357

AC:

AN:

111966

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34152

show subpopulations

Gnomad4 AFR

AF:

0.000130

AC:

0.000129866

AN:

0.000129866

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Sep 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

SLC35A2-congenital disorder of glycosylation

Uncertain:1

May 15, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC35A2 protein function. ClinVar contains an entry for this variant (Variation ID: 1449924). This missense change has been observed in individual(s) with clinical features of SLC35A2-related conditions (Invitae). This variant is present in population databases (rs782516328, gnomAD 0.01%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 367 of the SLC35A2 protein (p.Gln367Arg). -

Inborn genetic diseases

Benign:1

Dec 03, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.15

T;.;.;T;.

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.018

MetaRNN

Benign

0.093

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;.;.;.

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.10

N;N;.;.;N

REVEL

Benign

0.071

Sift

Benign

0.065

T;D;.;.;D

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.0

B;B;.;B;.

Vest4

0.12

MVP

0.14

MPC

1.4

ClinPred

0.038

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.41

Mutation Taster

=89/11

polymorphism

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