19-17555753-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_024656.4(COLGALT1):c.40C>T(p.Pro14Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000568 in 1,214,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

COLGALT1
NM_024656.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.09

Variant links:

Genes affected

COLGALT1 (HGNC:26182): (collagen beta(1-O)galactosyltransferase 1) The protein encoded by this gene is one of two enzymes that transfers galactose moieties to hydroxylysine residues of collagen and mannose binding lectin. This gene is constitutively expressed and encodes a soluble protein that localizes to the endoplasmic reticulum. [provided by RefSeq, Dec 2015]

COLGALT1 links:

NIBAN3 (HGNC:24130): (niban apoptosis regulator 3)

NIBAN3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.030822933).

BP6

Variant 19-17555753-C-T is Benign according to our data. Variant chr19-17555753-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1973108.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000337 (51/151376) while in subpopulation AFR AF= 0.00111 (46/41434). AF 95% confidence interval is 0.000855. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLGALT1	NM_024656.4 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 12	ENST00000252599.9	NP_078932.2	Q8NBJ5
COLGALT1	XM_005260080.5 link	c.-783C>T		upstream_gene_variant			XP_005260137.1
NIBAN3	XM_011527786.3 link	c.*594C>T		downstream_gene_variant			XP_011526088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COLGALT1	ENST00000252599.9 link	c.40C>T	p.Pro14Ser	missense_variant	Exon 1 of 12	1	NM_024656.4	ENSP00000252599.3		Q8NBJ5

Frequencies

GnomAD3 genomes

AF:

0.000331

AC:

AN:

151268

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000264

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:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000169

AC:

AN:

1063540

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

502694

show subpopulations

Gnomad4 AFR exome

AF:

0.000407

Gnomad4 AMR exome

AF:

0.000388

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000142

GnomAD4 genome

AF:

0.000337

AC:

AN:

151376

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

73984

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.000264

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000389

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 14 of the COLGALT1 protein (p.Pro14Ser). This variant is present in population databases (no rsID available, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with COLGALT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1973108). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Not Available"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Benign:1

Jan 23, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.56

CADD

Benign

6.6

DANN

Benign

0.94

DEOGEN2

Benign

0.016

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.33

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.031

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.69

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.33

REVEL

Benign

0.11

Sift

Benign

1.0

Sift4G

Benign

0.67

Polyphen

0.0

Vest4

0.050

MutPred

0.22

Gain of helix (P = 0.0078);

MVP

0.095

MPC

0.29

ClinPred

0.11

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.018

gMVP

0.61

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