chrX-120626774-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). 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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2B:5

Conservation

PhyloP100: -0.137

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature
Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics, ClinGen

C1GALT1C1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011901557).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

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.393T>A	p.Asp131Glu	missense	Exon 2 of 2	NP_001011551.1	Q96EU7
	C1GALT1C1	NM_152692.5		c.393T>A	p.Asp131Glu	missense	Exon 3 of 3	NP_689905.1	Q96EU7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
C1GALT1C1	ENST00000304661.6	TSL:1 MANE Select	c.393T>A	p.Asp131Glu	missense	Exon 2 of 2	ENSP00000304364.5	Q96EU7
C1GALT1C1	ENST00000371313.2	TSL:1	c.393T>A	p.Asp131Glu	missense	Exon 3 of 3	ENSP00000360363.2	Q96EU7
C1GALT1C1	ENST00000899457.1		c.393T>A	p.Asp131Glu	missense	Exon 2 of 2	ENSP00000569516.1

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

18155

AN:

111450

Hom.:

1383

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.199

AC:

36224

AN:

181667

AF XY:

0.216

show subpopulations

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 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.:

AF XY:

0.227

AC XY:

82325

AN XY:

361878

show subpopulations

African (AFR)

AF:

0.0279

AC:

735

AN:

26346

American (AMR)

AF:

0.159

AC:

5551

AN:

35010

Ashkenazi Jewish (ASJ)

AF:

0.164

AC:

3174

AN:

19332

East Asian (EAS)

AF:

0.100

AC:

3019

AN:

30145

South Asian (SAS)

AF:

0.290

AC:

15693

AN:

54050

European-Finnish (FIN)

AF:

0.233

AC:

9419

AN:

40493

Middle Eastern (MID)

AF:

0.188

AC:

776

AN:

4121

European-Non Finnish (NFE)

AF:

0.234

AC:

196770

AN:

840800

Other (OTH)

AF:

0.218

AC:

10025

AN:

46003

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

7715

15430

23144

30859

38574

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

7054

14108

21162

28216

35270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.163

AC:

18150

AN:

111504

Hom.:

1382

Cov.:

AF XY:

0.156

AC XY:

5268

AN XY:

33686

show subpopulations

African (AFR)

AF:

0.0353

AC:

1091

AN:

30875

American (AMR)

AF:

0.161

AC:

1680

AN:

10434

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

431

AN:

2640

East Asian (EAS)

AF:

0.117

AC:

417

AN:

3566

South Asian (SAS)

AF:

0.272

AC:

727

AN:

2676

European-Finnish (FIN)

AF:

0.212

AC:

1254

AN:

5921

Middle Eastern (MID)

AF:

0.174

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.230

AC:

12166

AN:

52982

Other (OTH)

AF:

0.165

AC:

249

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

538

1076

1613

2151

2689

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Polyagglutinable erythrocyte syndrome (4)

C1GALT1C1-related disorder (1)

Hemolytic uremic syndrome, atypical, 8, with rhizomelic short stature (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.0

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.075

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.45

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.45

PhyloP100

-0.14

PrimateAI

Benign

0.44

PROVEAN

Benign

0.25

REVEL

Benign

0.27

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.029

MutPred

0.14

Gain of ubiquitination at K132 (P = 0.107)

MPC

0.26

ClinPred

0.0049

GERP RS

1.5

Varity_R

0.052

gMVP

0.45

Mutation Taster

=94/6

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over