rs1557043131

Positions:

• chrX-48906469-CT-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_005660.3(SLC35A2):​c.348del​(p.Val117CysfsTer27) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC35A2 NM_005660.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.574

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-48906469-CT-C is Pathogenic according to our data. Variant chrX-48906469-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 541105.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-48906469-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC35A2	NM_005660.3	c.348del	p.Val117CysfsTer27	frameshift_variant	3/5	ENST00000247138.11	NP_005651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC35A2	ENST00000247138.11	c.348del	p.Val117CysfsTer27	frameshift_variant	3/5	1	NM_005660.3	ENSP00000247138	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

SLC35A2-congenital disorder of glycosylation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the SLC35A2 protein in which other variant(s) (p.Phe324Leufs*25) have been determined to be pathogenic (PMID: 24115232). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 541105). This premature translational stop signal has been observed in individual(s) with SLC35A2-related conditions (PMID: 30817854). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Val117Cysfs*27) in the SLC35A2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 277 amino acid(s) of the SLC35A2 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1557043131; hg19: chrX-48763746;