rs55816283
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000091.5(COL4A3):c.3325C>T(p.Pro1109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,613,784 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000091.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00415 AC: 632AN: 152178Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00430 AC: 1072AN: 249366Hom.: 6 AF XY: 0.00458 AC XY: 620AN XY: 135318
GnomAD4 exome AF: 0.00621 AC: 9070AN: 1461488Hom.: 44 Cov.: 31 AF XY: 0.00613 AC XY: 4460AN XY: 727056
GnomAD4 genome AF: 0.00414 AC: 631AN: 152296Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296AN XY: 74462
ClinVar
Submissions by phenotype
not specified Benign:4
Variant summary: COL4A3 c.3325C>T (p.Pro1109Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) 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 0.0042 in 280758 control chromosomes with 7 homozygotes (gnomAD), occuring predominantly at a frequency of 0.0057 within the Non-Finnish European subpopulation in the gnomAD database with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3325C>T has been reported in the literature in individuals affected with Kidney Disorders (Longo_2002, Wang_2004, Papazachariou_2014, Kovacs_2016), often times reported as a polymorphism due to its heterozygosity index (Wang_2004), high mean allele frequency (Papazachariou_2014), or other variants being causitive of disease (Kovacs_2016). These reports suggest the variant is not likely to be associated with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign. -
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p.Pro1109Ser in exon 38 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 0.56% (376/66566) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs55816283). -
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not provided Benign:4
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This variant is associated with the following publications: (PMID: 14871398, 12028435, 17216251, 29981437) -
COL4A3: BS2 -
Alport syndrome Uncertain:1
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Kidney disorder Benign:1
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COL4A3-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at