rs137853598

Variant names:

• chrX-120626965-G-A
• rs137853598
• NM_001011551.3:c.202C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001011551.3(C1GALT1C1):​c.202C>T​(p.Arg68*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: C1GALT1C1 NM_001011551.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.72

Genes affected

C1GALT1C1 (HGNC:24338): (C1GALT1 specific chaperone 1) This gene encodes a type II transmembrane protein that is similar to the core 1 beta1,3-galactosyltransferase 1, which catalyzes the synthesis of the core-1 structure, also known as Thomsen-Friedenreich antigen, on O-linked glycans. This gene product lacks the galactosyltransferase activity itself, but instead acts as a molecular chaperone required for the folding, stability and full activity of the core 1 beta1,3-galactosyltransferase 1. Mutations in this gene have been associated with Tn syndrome. Alternatively spliced transcript variants encoding the same protein have been identified. [provided by RefSeq, Dec 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.789 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120626965-G-A is Pathogenic according to our data. Variant chrX-120626965-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10791.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C1GALT1C1	NM_001011551.3	c.202C>T	p.Arg68*	stop_gained	Exon 2 of 2	ENST00000304661.6	NP_001011551.1
C1GALT1C1	NM_152692.5	c.202C>T	p.Arg68*	stop_gained	Exon 3 of 3		NP_689905.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C1GALT1C1	ENST00000304661.6	c.202C>T	p.Arg68*	stop_gained	Exon 2 of 2	1	NM_001011551.3	ENSP00000304364.5
C1GALT1C1	ENST00000371313.2	c.202C>T	p.Arg68*	stop_gained	Exon 3 of 3	1		ENSP00000360363.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Polyagglutinable erythrocyte syndrome Pathogenic:2

Oct 27, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 14, 2019

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant found in exon 3 of 3 is predicted to result in loss of normal protein function. This variant has been previously reported as a somatic change in patients with Tn Syndrome (PMID: 16251947). Functional characterization of the p.Arg68Ter indicated that the mutant protein resulted in less than 10% of T-synthase activity relative to wild type (PMID: 16251947). It is absent from the ExAC and gnomAD population databases and thus is presumed to be rare. Based on the available evidence, the c.202C>T, p.Arg68Ter variant is classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
Vest4		0.84
GERP RS		5.8

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: rs137853598; hg19: chrX-119760820; COSMIC: COSV58974430;