2-227164727-A-C
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_000091.5(COL4A3):c.1A>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,792 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 Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
COL4A3
NM_000091.5 start_lost
NM_000091.5 start_lost
Scores
4
2
10
Clinical Significance
Conservation
PhyloP100: 1.39
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 Pathogenic. Variant got 20 ACMG points.
PVS1
?
Start lost variant, no new inframe start found.
PS1
?
Another start lost variant in NM_000091.5 (COL4A3) was described as [Likely_pathogenic] in ClinVar as 556991
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 2-227164727-A-C is Pathogenic according to our data. Variant chr2-227164727-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555012.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.1A>C | p.Met1? | start_lost | 1/52 | ENST00000396578.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.1A>C | p.Met1? | start_lost | 1/52 | 1 | NM_000091.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 32
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GnomAD4 exome Cov.: 31
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GnomAD4 genome ? AF: 0.00000659 AC: 1AN: 151792Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74140
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 13, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is not observed in the gnomAD v2.1.1 dataset. Start-lost: reinitiation of translation may occur at a downstream alternate start codon but still result in a loss or disruption of normal protein function as there have been pathogenic variants reported upstream of the alterante start codon. The variant has been reported at least twice as pathogenic (ClinVar ID: VCV000555012). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 14, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 555012). Disruption of the initiator codon has been observed in individuals with autosomal recessive Alport syndrome (PMID: 12028435, 23297803, 24854265, 26809805). This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the COL4A3 mRNA. The next in-frame methionine is located at codon 209. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationTaster
Benign
D
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of catalytic residue at M1 (P = 0.1047);
MVP
ClinPred
T
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