rs104886050
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong
The NM_033380.3(COL4A5):c.1A>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 20)
Consequence
COL4A5
NM_033380.3 start_lost
NM_033380.3 start_lost
Scores
5
5
3
Clinical Significance
Conservation
PhyloP100: 3.78
Genes affected
COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. 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. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 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_033380.3 (COL4A5) was described as [Pathogenic] in ClinVar as 2770173
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-108440126-A-G is Pathogenic according to our data. Variant chrX-108440126-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 24214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-108440126-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.1A>G | p.Met1? | start_lost | 1/53 | ENST00000328300.11 | |
COL4A5 | NM_000495.5 | c.1A>G | p.Met1? | start_lost | 1/51 | ||
COL4A5 | XM_047441811.1 | c.1A>G | p.Met1? | start_lost | 1/42 | ||
COL4A5 | XM_047441810.1 | c.-376A>G | 5_prime_UTR_variant | 1/54 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.1A>G | p.Met1? | start_lost | 1/53 | 1 | NM_033380.3 |
Frequencies
GnomAD3 genomes ? Cov.: 20
GnomAD3 genomes
?
Cov.:
20
GnomAD4 exome Cov.: 29
GnomAD4 exome
Cov.:
29
GnomAD4 genome ? Cov.: 20
GnomAD4 genome
?
Cov.:
20
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 04, 2020 | This sequence change affects the initiator methionine of the COL4A5 mRNA. The next in-frame methionine is located at codon 109. This variant is not present in population databases (ExAC no frequency). Disruption of this initiator codon has been observed in individual(s) with Alport syndrome (PMID: 24033287, Invitae). ClinVar contains an entry for this variant (Variation ID: 24214). This variant disrupts the p.Gly105 amino acid residue in COL4A5. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
X-linked Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Apr 30, 2020 | This variant is predicted to abolish the native initation codon of COL4A5 and has been previously reported in a patient presenting with presumed X-linked dominant Alport syndrome (end stage-renal disease, family history of similar presentations, no information about hearing). Additionally, this COL4A5 variant is absent from a large population dataset. We consider this variant to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
A;A
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
0.32
.;B
Vest4
MutPred
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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