19-17555753-C-T

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

2
17

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

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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
COLGALT1NM_024656.4 linkc.40C>T p.Pro14Ser missense_variant Exon 1 of 12 ENST00000252599.9 NP_078932.2 Q8NBJ5
COLGALT1XM_005260080.5 linkc.-783C>T upstream_gene_variant XP_005260137.1
NIBAN3XM_011527786.3 linkc.*594C>T downstream_gene_variant XP_011526088.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COLGALT1ENST00000252599.9 linkc.40C>T p.Pro14Ser missense_variant Exon 1 of 12 1 NM_024656.4 ENSP00000252599.3 Q8NBJ5

Frequencies

GnomAD3 genomes
AF:
0.000331
AC:
50
AN:
151268
Hom.:
0
Cov.:
31
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:
18
AN:
1063540
Hom.:
0
Cov.:
29
AF XY:
0.0000179
AC XY:
9
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:
51
AN:
151376
Hom.:
0
Cov.:
31
AF XY:
0.000324
AC XY:
24
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.:
0
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
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
6.6
DANN
Benign
0.94
DEOGEN2
Benign
0.016
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.046
N
LIST_S2
Benign
0.33
T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.031
T
MetaSVM
Benign
-0.92
T
MutationAssessor
Benign
-0.69
N
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
0.33
N
REVEL
Benign
0.11
Sift
Benign
1.0
T
Sift4G
Benign
0.67
T
Polyphen
0.0
B
Vest4
0.050
MutPred
0.22
Gain of helix (P = 0.0078);
MVP
0.095
MPC
0.29
ClinPred
0.11
T
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.

Other links and lift over

dbSNP: rs955092262; hg19: chr19-17666562; API