rs104886285
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1BS2_Supporting
The NM_033380.3(COL4A5):c.4550G>A(p.Arg1517His) variant causes a missense change. The variant allele was found at a frequency of 0.0000165 in 1,209,389 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 2 hem., cov: 22)
Exomes 𝑓: 0.000016 ( 0 hom. 3 hem. )
Consequence
COL4A5
NM_033380.3 missense
NM_033380.3 missense
Scores
5
7
5
Clinical Significance
Conservation
PhyloP100: 4.84
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 Uncertain_significance. Variant got 1 ACMG points.
PM1
In a domain Collagen IV NC1 (size 224) in uniprot entity CO4A5_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_033380.3
BS2
High Hemizygotes in GnomAd4 at 2 XL geneVariant has number of hemizygotes 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/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL4A5 | NM_033380.3 | c.4550G>A | p.Arg1517His | missense_variant | 50/53 | ENST00000328300.11 | NP_203699.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.4550G>A | p.Arg1517His | missense_variant | 50/53 | 1 | NM_033380.3 | ENSP00000331902.7 | ||
COL4A5 | ENST00000361603.7 | c.4532G>A | p.Arg1511His | missense_variant | 48/51 | 2 | ENSP00000354505.2 | |||
COL4A5 | ENST00000515658.1 | c.323-3528G>A | intron_variant | 5 | ENSP00000423520.1 | |||||
COL4A5 | ENST00000510690.2 | n.1044G>A | non_coding_transcript_exon_variant | 8/11 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000179 AC: 2AN: 111497Hom.: 0 Cov.: 22 AF XY: 0.0000594 AC XY: 2AN XY: 33665
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GnomAD3 exomes AF: 0.0000164 AC: 3AN: 182911Hom.: 0 AF XY: 0.0000148 AC XY: 1AN XY: 67529
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GnomAD4 exome AF: 0.0000164 AC: 18AN: 1097892Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 3AN XY: 363304
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GnomAD4 genome AF: 0.0000179 AC: 2AN: 111497Hom.: 0 Cov.: 22 AF XY: 0.0000594 AC XY: 2AN XY: 33665
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2023 | Variant summary: COL4A5 c.4532G>A (p.Arg1511His) results in a non-conservative amino acid change located in the Collagen IV, non-collagenous domain (IPR001442) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 (i.e., 3 heterozygous carriers, including 2 females and 1 male) in 182911 control chromosomes (gnomAD v2, Exomes cohort). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4532G>A has been reported in the literature in individuals affected with Alport Syndrome (e.g., Plant_1999, Cheong_2000, Azaiez_2018, Zhao_2019, Park_2020), however, the variant was also reported in an asymptomatic male (Zhao_2019). Therefore these data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant disrupts type IV collagen heterotrimer formation but was still found to be secreted by cells (e.g., Kobayashi_2008). The following publications have been ascertained in the context of this evaluation (PMID: 30245029, 10684360, 18083113, 32604935, 10094548, 30968591). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 13, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
.;D
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
.;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Benign
D;D
Sift4G
Benign
T;T
Polyphen
0.73
.;P
Vest4
MVP
MPC
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