rs17261572

chrX-120626774-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001011551.3(C1GALT1C1):c.393T>A(p.Asp131Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,207,804 control chromosomes in the GnomAD database, including 20,280 homozygotes. There are 87,593 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D131N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (1382 hom., 5268 hem., cov: 23)
  • Exomes 𝑓: 0.22 (18898 hom. 82325 hem.)
• Consequence: C1GALT1C1 NM_001011551.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -0.137

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0011901557).
• BP6: Variant X-120626774-A-T is Benign according to our data. Variant chrX-120626774-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 10792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1GALT1C1	NM_001011551.3	c.393T>A	p.Asp131Glu	missense_variant	2/2	ENST00000304661.6
C1GALT1C1	NM_152692.5	c.393T>A	p.Asp131Glu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1GALT1C1	ENST00000304661.6	c.393T>A	p.Asp131Glu	missense_variant	2/2	1	NM_001011551.3	P1
C1GALT1C1	ENST00000371313.2	c.393T>A	p.Asp131Glu	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.163 AC: 18155 AN: 111450 Hom.: 1383 Cov.: 23 AF XY: 0.157 AC XY: 5265 AN XY: 33622

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.163

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.161

GnomAD3 exomes AF: 0.199 AC: 36224 AN: 181667 Hom.: 2312 AF XY: 0.216 AC XY: 14310 AN XY: 66393

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.160

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.124

Gnomad SAS exome AF: 0.286

Gnomad FIN exome AF: 0.231

Gnomad NFE exome AF: 0.229

Gnomad OTH exome AF: 0.202

GnomAD4 exome AF: 0.224 AC: 245162 AN: 1096300 Hom.: 18898 Cov.: 33 AF XY: 0.227 AC XY: 82325 AN XY: 361878

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.159

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.100

Gnomad4 SAS exome AF: 0.290

Gnomad4 FIN exome AF: 0.233

Gnomad4 NFE exome AF: 0.234

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.163 AC: 18150 AN: 111504 Hom.: 1382 Cov.: 23 AF XY: 0.156 AC XY: 5268 AN XY: 33686

Gnomad4 AFR AF: 0.0353

Gnomad4 AMR AF: 0.161

Gnomad4 ASJ AF: 0.163

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.165

Alfa AF: 0.213 Hom.: 5927

Bravo AF: 0.150

TwinsUK AF: 0.243 AC: 900

ALSPAC AF: 0.239 AC: 691

ESP6500AA AF: 0.0407 AC: 156

ESP6500EA AF: 0.228 AC: 1532

ExAC AF: 0.202 AC: 24517

EpiCase AF: 0.221

EpiControl AF: 0.231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyagglutinable erythrocyte syndrome Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 27, 2005	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 10, 2021	- -

C1GALT1C1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	6.0
Dann	Benign	0.61
DEOGEN2	Benign	0.075	T;T
FATHMM_MKL	Benign	0.31	N
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.45	N;N
MutationTaster	Benign	0.46	P;P
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.25	N;N
REVEL	Benign	0.27
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.029
MutPred		0.14		Gain of ubiquitination at K132 (P = 0.107);Gain of ubiquitination at K132 (P = 0.107);
MPC		0.26
ClinPred		0.0049	T
GERP RS		1.5
Varity_R		0.052
gMVP		0.45

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: rs17261572; hg19: chrX-119760629; COSMIC: COSV58973748;