rs80109666
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000091.5(COL4A3):c.805G>A(p.Glu269Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,684 control chromosomes in the GnomAD database, including 734 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E269E) has been classified as Likely benign.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.805G>A | p.Glu269Lys | missense_variant | 14/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.1592+5027C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.805G>A | p.Glu269Lys | missense_variant | 14/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.1592+5027C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes AF: 0.0293 AC: 4460AN: 152098Hom.: 164 Cov.: 32
GnomAD3 exomes AF: 0.0232 AC: 5790AN: 249418Hom.: 284 AF XY: 0.0214 AC XY: 2894AN XY: 135310
GnomAD4 exome AF: 0.00999 AC: 14606AN: 1461468Hom.: 570 Cov.: 31 AF XY: 0.00994 AC XY: 7226AN XY: 727076
GnomAD4 genome AF: 0.0293 AC: 4465AN: 152216Hom.: 164 Cov.: 32 AF XY: 0.0306 AC XY: 2276AN XY: 74440
ClinVar
Submissions by phenotype
not provided Benign:5
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 06, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 21, 2016 | p.Glu269Lys in exon 14 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 15.00% (1291/8608) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs80109666). - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 05, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2019 | Variant summary: COL4A3 c.805G>A (p.Glu269Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.023 in 249418 control chromosomes, predominantly at a frequency of 0.15 within the East Asian subpopulation in the gnomAD database, including 220 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 73-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, autosomal recessive phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.805G>A has been reported in the literature in an individual affected with Alport Syndrome, autosomal recessive, however, authors classify the variant as a polymorphism (Zhang_2012). Four ClinVar submissions (evaluation after 2014) cite the variant three times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. - |
Alport syndrome Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 01, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at