rs769683665
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000091.5(COL4A3):c.2962G>A(p.Gly988Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,200 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
COL4A3
NM_000091.5 missense
NM_000091.5 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 5.70
Genes affected
COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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, Jun 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000091.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.993
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.2962G>A | p.Gly988Arg | missense_variant | 35/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.244-7441C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.2962G>A | p.Gly988Arg | missense_variant | 35/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.244-7441C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 152060Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248514Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134800
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461140Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726834
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152060Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 74298
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Autosomal recessive Alport syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | Mar 01, 2023 | The missense variant c.2962G>A(p.Gly988Arg) in COL4A3 gene has been reported previously in heterozygous state with monogenic steroid-resistant nephrotic syndrome (Larisa Prikhodina, et al., 2021). The variant has 0.0004% allele frequency in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The amino acid Glycine at position 988 is changed to a Arginine changing protein sequence and it might alter its composition and physico-chemical properties. This variant has been reported to the ClinVar database as Likely Pathogenic. However, study on multiple affected individuals and functional impact of the variant is not available. The variant is predicted to be damaging by SIFT. The amino acid change p.Gly988Arg in COL4A3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of methylation at G988 (P = 0.0158);.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at