chr13-110306954-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001845.6(COL4A1):ā€‹c.74C>Gā€‹(p.Ala25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,322,156 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 Uncertain significance (ā˜…). Synonymous variant affecting the same amino acid position (i.e. A25A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000015 ( 0 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.678
Variant links:
Genes affected
COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]
COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL4A1. . Gene score misZ 3.0194 (greater than the threshold 3.09). Trascript score misZ 4.972 (greater than threshold 3.09). GenCC has associacion of gene with brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.
BP4
Computational evidence support a benign effect (MetaRNN=0.20188242).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL4A1NM_001845.6 linkuse as main transcriptc.74C>G p.Ala25Gly missense_variant 1/52 ENST00000375820.10
COL4A1NM_001303110.2 linkuse as main transcriptc.74C>G p.Ala25Gly missense_variant 1/25

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL4A1ENST00000375820.10 linkuse as main transcriptc.74C>G p.Ala25Gly missense_variant 1/521 NM_001845.6 P1P02462-1
COL4A1ENST00000543140.6 linkuse as main transcriptc.74C>G p.Ala25Gly missense_variant 1/251 P02462-2
COL4A2ENST00000400163.7 linkuse as main transcriptc.-44-906G>C intron_variant 5
COL4A1ENST00000649738.1 linkuse as main transcriptn.204C>G non_coding_transcript_exon_variant 1/31

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.0000119
AC:
1
AN:
84302
Hom.:
0
AF XY:
0.0000209
AC XY:
1
AN XY:
47772
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000572
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000151
AC:
2
AN:
1322156
Hom.:
0
Cov.:
30
AF XY:
0.00000307
AC XY:
2
AN XY:
651042
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000275
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeApr 22, 2022This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 25 of the COL4A1 protein (p.Ala25Gly). This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL4A1 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.086
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Benign
0.33
T;.
Eigen
Benign
-0.43
Eigen_PC
Benign
-0.36
FATHMM_MKL
Benign
0.55
D
LIST_S2
Benign
0.61
T;T
M_CAP
Pathogenic
0.95
D
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Benign
0.34
N;N
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.0
N;N
REVEL
Benign
0.25
Sift
Benign
0.34
T;T
Sift4G
Benign
0.33
T;T
Polyphen
0.49
P;.
Vest4
0.094
MutPred
0.46
Gain of catalytic residue at G30 (P = 0.001);Gain of catalytic residue at G30 (P = 0.001);
MVP
0.53
MPC
0.39
ClinPred
0.10
T
GERP RS
1.4
Varity_R
0.035
gMVP
0.32

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: rs1188718847; hg19: chr13-110959301; API