X-120626501-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001011551.3(C1GALT1C1):c.666G>C(p.Gln222His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,210,871 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 175 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.00033 (0 hom. 167 hem.)
• Consequence: C1GALT1C1 NM_001011551.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.46

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052019745).
• BP6: Variant X-120626501-C-G is Benign according to our data. Variant chrX-120626501-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2051173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1GALT1C1	NM_001011551.3	c.666G>C	p.Gln222His	missense_variant	2/2	ENST00000304661.6
C1GALT1C1	NM_152692.5	c.666G>C	p.Gln222His	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1GALT1C1	ENST00000304661.6	c.666G>C	p.Gln222His	missense_variant	2/2	1	NM_001011551.3	P1
C1GALT1C1	ENST00000371313.2	c.666G>C	p.Gln222His	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.000222 AC: 25 AN: 112692 Hom.: 0 Cov.: 24 AF XY: 0.000230 AC XY: 8 AN XY: 34834

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00286

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000319

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000393 AC: 72 AN: 183344 Hom.: 0 AF XY: 0.000560 AC XY: 38 AN XY: 67820

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000325 AC: 357 AN: 1098124 Hom.: 0 Cov.: 31 AF XY: 0.000459 AC XY: 167 AN XY: 363498

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00181

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.000325

GnomAD4 genome AF: 0.000222 AC: 25 AN: 112747 Hom.: 0 Cov.: 24 AF XY: 0.000229 AC XY: 8 AN XY: 34899

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00287

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000319

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000397 Hom.: 10

Bravo AF: 0.000200

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000692 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000273

EpiControl AF: 0.000652

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polyagglutinable erythrocyte syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

- -

C1GALT1C1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 23, 2023

This variant is classified as likely 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	Pathogenic	0.73
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.48	T;T
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.012	D;D
Polyphen		0.32	B;B
Vest4		0.28
MutPred		0.67		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.85
MPC		0.93
ClinPred		0.15	T
GERP RS		3.7
Varity_R		0.64
gMVP		0.95

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: rs200973382; hg19: chrX-119760356;