rs1557044030

Variant names:

• chrX-48911498-GATCCCGACCTCCGCCTCCCATGCGACTGCTCGGGCAGACTGTCTCACCCGCACTGGCGGTCCCCGGCTCCAATGCACCCGCGGAAACCGCCCCTGGCCCGGGCGCCGCGGTGGAACCACCAGCC-T
• rs1557044030
• NM_005660.3:c.15_91+48delGGCTGGTGGTTCCACCGCGGCGCCCGGGCCAGGGGCGGTTTCCGCGGGTGCATTGGAGCCGGGGACCGCCAGTGCGGGTGAGACAGTCTGCCCGAGCAGTCGCATGGGAGGCGGAGGTCGGGATCinsA

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_005660.3(SLC35A2):​c.15_91+48delGGCTGGTGGTTCCACCGCGGCGCCCGGGCCAGGGGCGGTTTCCGCGGGTGCATTGGAGCCGGGGACCGCCAGTGCGGGTGAGACAGTCTGCCCGAGCAGTCGCATGGGAGGCGGAGGTCGGGATCinsA​(p.Ala6fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: SLC35A2 NM_005660.3 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.689
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 48 pathogenic variants in the truncated region.
• PP5: Variant X-48911498-GATCCCGACCTCCGCCTCCCATGCGACTGCTCGGGCAGACTGTCTCACCCGCACTGGCGGTCCCCGGCTCCAATGCACCCGCGGAAACCGCCCCTGGCCCGGGCGCCGCGGTGGAACCACCAGCC-T is Pathogenic according to our data. Variant chrX-48911498-GATCCCGACCTCCGCCTCCCATGCGACTGCTCGGGCAGACTGTCTCACCCGCACTGGCGGTCCCCGGCTCCAATGCACCCGCGGAAACCGCCCCTGGCCCGGGCGCCGCGGTGGAACCACCAGCC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 50363.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC35A2	NM_005660.3	c.15_91+48delGGCTGGTGGTTCCACCGCGGCGCCCGGGCCAGGGGCGGTTTCCGCGGGTGCATTGGAGCCGGGGACCGCCAGTGCGGGTGAGACAGTCTGCCCGAGCAGTCGCATGGGAGGCGGAGGTCGGGATCinsA	p.Ala6fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 5	ENST00000247138.11	NP_005651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC35A2	ENST00000247138.11	c.15_91+48delGGCTGGTGGTTCCACCGCGGCGCCCGGGCCAGGGGCGGTTTCCGCGGGTGCATTGGAGCCGGGGACCGCCAGTGCGGGTGAGACAGTCTGCCCGAGCAGTCGCATGGGAGGCGGAGGTCGGGATCinsA	p.Ala6fs	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 5	1	NM_005660.3	ENSP00000247138.5

Frequencies

GnomAD3 genomes Cov.: 24

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

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

SLC35A2-congenital disorder of glycosylation Pathogenic:2

Nov 14, 2013

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Apr 04, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1557044030; hg19: chrX-48768775;