rs140079332

chrX-48904951-C-AchrX-48904951-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_005660.3(SLC35A2):c.958G>T(p.Val320Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,466 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V320M) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: SLC35A2 NM_005660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity S35A2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_005660.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07769337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC35A2	NM_005660.3	c.958G>T	p.Val320Leu	missense_variant	4/5	ENST00000247138.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC35A2	ENST00000247138.11	c.958G>T	p.Val320Leu	missense_variant	4/5	1	NM_005660.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112084 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34262

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097382 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112084 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34262

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLC35A2-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

This sequence change replaces valine with leucine at codon 320 of the SLC35A2 protein (p.Val320Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with SLC35A2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	Benign	0.16
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	15
Dann	Benign	0.84
DEOGEN2	Benign	0.25	T;.;.;T;.
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.078	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.015	N;N;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.53	N;N;.;.;N
REVEL	Benign	0.047
Sift	Benign	1.0	T;T;.;.;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.0030	B;B;.;B;.
Vest4		0.20
MutPred		0.69		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;
MVP		0.15
MPC		0.88
ClinPred		0.051	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.78

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

Other links and lift over

dbSNP: rs140079332; hg19: chrX-48762228;