chrX-120626412-C-A

Variant names:

• chrX-120626412-C-A
• rs146957987
• NM_001011551.3:c.755G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001011551.3(C1GALT1C1):​c.755G>T​(p.Gly252Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,776 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G252E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: C1GALT1C1 NM_001011551.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.27
• Publications: 0 publications found

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]

C1GALT1C1 Gene-Disease associations (from GenCC):

• hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17389187).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001011551.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1GALT1C1	NM_001011551.3	MANE Select	c.755G>T	p.Gly252Val	missense	Exon 2 of 2	NP_001011551.1	Q96EU7
	C1GALT1C1	NM_152692.5		c.755G>T	p.Gly252Val	missense	Exon 3 of 3	NP_689905.1	Q96EU7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C1GALT1C1	ENST00000304661.6	TSL:1 MANE Select	c.755G>T	p.Gly252Val	missense	Exon 2 of 2	ENSP00000304364.5	Q96EU7
	C1GALT1C1	ENST00000371313.2	TSL:1	c.755G>T	p.Gly252Val	missense	Exon 3 of 3	ENSP00000360363.2	Q96EU7
	C1GALT1C1	ENST00000899457.1		c.755G>T	p.Gly252Val	missense	Exon 2 of 2	ENSP00000569516.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097776 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000379 AC: 1 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00 AC: 0 AN: 54115

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841793

Other (OTH) AF: 0.00 AC: 0 AN: 46078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.88	L
PhyloP100		2.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.11
Sift	Benign	0.18	T
Sift4G	Uncertain	0.031	D
Polyphen		0.065	B
Vest4		0.13
MutPred		0.46		Loss of helix (P = 0.0558)
MVP		0.68
MPC		0.35
ClinPred		0.21	T
GERP RS		5.5
Varity_R		0.33
gMVP		0.81
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs146957987; hg19: chrX-119760267;