chrX-48905474-GTA-G

Variant names:

• chrX-48905474-GTA-G
• rs587777434
• NM_005660.3:c.433_434delTA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005660.3(SLC35A2):​c.433_434delTA​(p.Tyr145ProfsTer76) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: SLC35A2 NM_005660.3 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.29
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• SLC35A2-congenital disorder of glycosylation

  Inheritance: XL, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 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-48905474-GTA-G is Pathogenic according to our data. Variant chrX-48905474-GTA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 135674.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005660.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A2	NM_005660.3	MANE Select	c.433_434delTA	p.Tyr145ProfsTer76	frameshift	Exon 4 of 5	NP_005651.1
	SLC35A2	NM_001282651.2		c.517_518delTA	p.Tyr173ProfsTer76	frameshift	Exon 5 of 5	NP_001269580.1
	SLC35A2	NM_001282650.2		c.472_473delTA	p.Tyr158ProfsTer76	frameshift	Exon 4 of 4	NP_001269579.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC35A2	ENST00000247138.11	TSL:1 MANE Select	c.433_434delTA	p.Tyr145ProfsTer76	frameshift	Exon 4 of 5	ENSP00000247138.5
	SLC35A2	ENST00000376521.6	TSL:1	c.433_434delTA	p.Tyr145ProfsTer76	frameshift	Exon 4 of 4	ENSP00000365704.1
	SLC35A2	ENST00000445167.7	TSL:1	c.427-584_427-583delTA		intron	N/A	ENSP00000402726.2

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	SLC35A2-congenital disorder of glycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587777434; hg19: chrX-48762751;