13-110192845-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4BS2_Supporting

The NM_001845.6(COL4A1):​c.1450C>G​(p.Pro484Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

2
10
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.82
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PP2
Missense variant in the COL4A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 194 curated pathogenic missense variants (we use a threshold of 10). The gene has 77 curated benign missense variants. Gene score misZ: 3.0194 (below the threshold of 3.09). Trascript score misZ: 4.972 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.36324728).
BS2
High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A1NM_001845.6 linkc.1450C>G p.Pro484Ala missense_variant Exon 23 of 52 ENST00000375820.10 NP_001836.3
COL4A1NM_001303110.2 linkc.1450C>G p.Pro484Ala missense_variant Exon 23 of 25 NP_001290039.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A1ENST00000375820.10 linkc.1450C>G p.Pro484Ala missense_variant Exon 23 of 52 1 NM_001845.6 ENSP00000364979.4 P02462-1
COL4A1ENST00000543140.6 linkc.1450C>G p.Pro484Ala missense_variant Exon 23 of 25 1 ENSP00000443348.1 P02462-2
COL4A1ENST00000649738.1 linkn.1580C>G non_coding_transcript_exon_variant Exon 23 of 31

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461706
Hom.:
0
Cov.:
32
AF XY:
0.00000688
AC XY:
5
AN XY:
727174
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 20, 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 alanine, which is neutral and non-polar, at codon 484 of the COL4A1 protein (p.Pro484Ala). This variant is not present in population databases (gnomAD no frequency). 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 with a negative predictive value of 95%. 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
0.081
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
24
DANN
Benign
0.86
DEOGEN2
Pathogenic
0.83
D;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Uncertain
0.096
D
MetaRNN
Benign
0.36
T;T
MetaSVM
Uncertain
0.74
D
MutationAssessor
Benign
1.2
L;L
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-3.2
D;N
REVEL
Uncertain
0.55
Sift
Benign
0.52
T;T
Sift4G
Benign
0.54
T;T
Polyphen
0.83
P;.
Vest4
0.44
MutPred
0.48
Gain of catalytic residue at P479 (P = 2e-04);Gain of catalytic residue at P479 (P = 2e-04);
MVP
0.53
MPC
0.38
ClinPred
0.83
D
GERP RS
4.9
Varity_R
0.32
gMVP
0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-110845192; API