X-120626227-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001011551.3(C1GALT1C1):c.940G>C(p.Gly314Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000058 in 1,207,154 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

C1GALT1C1
NM_001011551.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.50

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17317975).

BS2

High Hemizygotes in GnomAdExome at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
C1GALT1C1	NM_001011551.3 linkuse as main transcript	c.940G>C	p.Gly314Arg	missense_variant	2/2	ENST00000304661.6
C1GALT1C1	NM_152692.5 linkuse as main transcript	c.940G>C	p.Gly314Arg	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
C1GALT1C1	ENST00000304661.6 linkuse as main transcript	c.940G>C	p.Gly314Arg	missense_variant	2/2	1	NM_001011551.3	P1
C1GALT1C1	ENST00000371313.2 linkuse as main transcript	c.940G>C	p.Gly314Arg	missense_variant	3/3	1		P1

Frequencies

GnomAD3 genomes

AF:

0.0000265

AC:

AN:

113074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35218

show subpopulations

Gnomad AFR

AF:

0.0000962

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000223

AC:

AN:

179618

Hom.:

AF XY:

0.0000466

AC XY:

AN XY:

64374

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000289

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000366

AC:

AN:

1094080

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359880

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000995

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000218

GnomAD4 genome

AF:

0.0000265

AC:

AN:

113074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35218

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.940G>C (p.G314R) alteration is located in exon 3 (coding exon 1) of the C1GALT1C1 gene. This alteration results from a G to C substitution at nucleotide position 940, causing the glycine (G) at amino acid position 314 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Polyagglutinable erythrocyte syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 849367). This variant has not been reported in the literature in individuals affected with C1GALT1C1-related conditions. This variant is present in population databases (rs749131756, gnomAD 0.03%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 314 of the C1GALT1C1 protein (p.Gly314Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.19

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.093

T;T

FATHMM_MKL

Pathogenic

0.99

M_CAP

Benign

0.076

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.14

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.74

P;P

Vest4

0.30

MutPred

0.12

Gain of catalytic residue at G314 (P = 0.0808);Gain of catalytic residue at G314 (P = 0.0808);

MVP

0.41

MPC

1.0

ClinPred

0.37

GERP RS

5.5

Varity_R

0.30

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over