2-227237964-C-T
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000091.5(COL4A3):c.88-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00441 in 1,608,052 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000091.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00771 AC: 1172AN: 152072Hom.: 37 Cov.: 32
GnomAD3 exomes AF: 0.0171 AC: 4275AN: 249508Hom.: 243 AF XY: 0.0131 AC XY: 1774AN XY: 135354
GnomAD4 exome AF: 0.00406 AC: 5912AN: 1455862Hom.: 292 Cov.: 27 AF XY: 0.00358 AC XY: 2597AN XY: 724672
GnomAD4 genome AF: 0.00771 AC: 1174AN: 152190Hom.: 36 Cov.: 32 AF XY: 0.00862 AC XY: 641AN XY: 74398
ClinVar
Submissions by phenotype
not specified Benign:6
c.88-4C>T in intron 1 of COL4A3: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence and h as been identified in 11.92% (1380/11576) of Latino chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148393022). -
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Variant summary: COL4A3 c.88-4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 277078 control chromosomes, predominantly at a frequency of 0.11 within the Latino subpopulation in the gnomAD database, including 235 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 54-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.88-4C>T in individuals affected with autosomal recessive Alport Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four 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 (3x) /likely benign (1x). 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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not provided Benign:2
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Alport syndrome Benign:2
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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. -
Focal segmental glomerulosclerosis Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at