rs113994109
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PP2PP3_StrongPP5_Moderate
The NM_001845.6(COL4A1):c.2245G>A(p.Gly749Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
COL4A1
NM_001845.6 missense
NM_001845.6 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 6.94
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 Pathogenic. Variant got 11 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001845.6
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, COL4A1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.985
PP5
?
Variant 13-110179370-C-T is Pathogenic according to our data. Variant chr13-110179370-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17413.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A1 | NM_001845.6 | c.2245G>A | p.Gly749Ser | missense_variant | 30/52 | ENST00000375820.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A1 | ENST00000375820.10 | c.2245G>A | p.Gly749Ser | missense_variant | 30/52 | 1 | NM_001845.6 | P1 | |
COL4A1 | ENST00000649738.1 | n.2375G>A | non_coding_transcript_exon_variant | 30/31 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461872Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727238
GnomAD4 exome
AF:
AC:
2
AN:
1461872
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
727238
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Brain small vessel disease 1 with or without ocular anomalies Pathogenic:2Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 20, 2005 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | May 06, 2020 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2023 | Reported in 3 members of a family with porencephaly (Gould et al., 2005; Gasparini et al, 2016); also identified in an unrelated infant with intracerebral hemorrhages, brain atrophy and ventriculomegaly and in his father with minor white matter abnormalities (Vermeulen et al., 2011); Affects a glycine residue in a Gly-X-Y motif in the triple helical region of the COL4A1 gene, where the majority of pathogenic missense variants occur, and is predicted to disrupt normal protein folding and function (Weng et al., 2012; Yoneda et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20166936, 17696175, 15905400, 15136694, 22914737, 33013618, 27794444, 30284656, 20818663, 26686511, 30413629, 21500141, 22522439, 23225343) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
A;A
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Gain of catalytic residue at L747 (P = 0);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at