rs1553758893
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000091.5(COL4A3):c.2031_2038dup(p.Gly680AspfsTer70) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,446,564 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G674G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000091.5 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL4A3 | NM_000091.5 | c.2031_2038dup | p.Gly680AspfsTer70 | frameshift_variant, splice_region_variant | 28/52 | ENST00000396578.8 | |
MFF-DT | NR_102371.1 | n.422+2032_422+2033insCCAGGGAT | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL4A3 | ENST00000396578.8 | c.2031_2038dup | p.Gly680AspfsTer70 | frameshift_variant, splice_region_variant | 28/52 | 1 | NM_000091.5 | P1 | |
MFF-DT | ENST00000439598.6 | n.422+2032_422+2033insCCAGGGAT | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000123 AC: 3AN: 244894Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132442
GnomAD4 exome AF: 0.0000118 AC: 17AN: 1446564Hom.: 0 Cov.: 29 AF XY: 0.0000181 AC XY: 13AN XY: 719996
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
Autosomal recessive Alport syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 04, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant has been observed in individual(s) with Alport syndrome (PMID: 24052634). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly680Aspfs*70) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at