NM_000091.5:c.73C>T
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000091.5(COL4A3):c.73C>T(p.Pro25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,518,396 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P25P) has been classified as Likely benign.
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
Publications
- Alport syndrome 3b, autosomal recessiveInheritance: AD, AR Classification: DEFINITIVE Submitted by: G2P
- autosomal recessive Alport syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet
- Alport syndromeInheritance: SD Classification: DEFINITIVE Submitted by: ClinGen
- autosomal dominant Alport syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
- hematuria, benign familial, 1Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Benign. The variant received -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00880 AC: 1339AN: 152084Hom.: 22 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00146 AC: 166AN: 113982 AF XY: 0.00124 show subpopulations
GnomAD4 exome AF: 0.000848 AC: 1159AN: 1366194Hom.: 16 Cov.: 31 AF XY: 0.000693 AC XY: 467AN XY: 673604 show subpopulations
GnomAD4 genome AF: 0.00880 AC: 1340AN: 152202Hom.: 22 Cov.: 32 AF XY: 0.00804 AC XY: 598AN XY: 74424 show subpopulations
ClinVar
Submissions by phenotype
not specified Benign:4
Variant summary: COL4A3 c.73C>T (p.Pro25Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 113982 control chromosomes, predominantly at a frequency of 0.04 within the African or African-American subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 20 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive phenotype (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.73C>T in individuals affected with Alport Syndrome, Autosomal Recessive and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
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. -
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p.Pro25Ser in exon 1 of COL4A3: This variant is not expected to have clinical si gnificance because it has been identified in 4.31% (57/1322) of African chromoso mes by the 1000 Genomes Project (Phase 3; dbSNP rs139271412). -
not provided Benign:2
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Kidney disorder Benign:1
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Alport syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at