NM_033380.3:c.2958_2975delGCCTGGAGACCCAGGGCA
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2PM4PP3PP5_Very_Strong
The NM_033380.3(COL4A5):c.2958_2975delGCCTGGAGACCCAGGGCA(p.Pro987_Gln992del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_033380.3 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL4A5 | ENST00000328300.11 | c.2958_2975delGCCTGGAGACCCAGGGCA | p.Pro987_Gln992del | disruptive_inframe_deletion | Exon 34 of 53 | 1 | NM_033380.3 | ENSP00000331902.7 | ||
COL4A5 | ENST00000483338.1 | c.1782_1799delGCCTGGAGACCCAGGGCA | p.Pro595_Gln600del | disruptive_inframe_deletion | Exon 18 of 20 | 1 | ENSP00000495685.1 | |||
COL4A5 | ENST00000361603.7 | c.2958_2975delGCCTGGAGACCCAGGGCA | p.Pro987_Gln992del | disruptive_inframe_deletion | Exon 34 of 51 | 2 | ENSP00000354505.2 | |||
COL4A5 | ENST00000505728.1 | c.189_206delGCCTGGAGACCCAGGGCA | p.Pro64_Gln69del | disruptive_inframe_deletion | Exon 2 of 5 | 3 | ENSP00000424137.1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
not provided Pathogenic:2
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the triple helix domain of COL4A5. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236). In COL4A5, missense variants at these glycine residues are significantly enriched in individuals with disease (PMID: 23720012, 27627812) compared to the general population (ExAC). ClinVar contains an entry for this variant (Variation ID: 520604). This variant is also known as 3161-3178del (del987-992). This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 10094548; Invitae). This variant is not present in population databases (ExAC no frequency). This variant, c.2958_2975del, results in the deletion of 6 amino acid(s) of the COL4A5 protein (p.Asp989_Gly994del), but otherwise preserves the integrity of the reading frame. -
In-frame deletion of six amino acids within the triple helical domain expected to disrupt normal protein folding and function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign in association with Alport syndrome to our knowledge; This variant is associated with the following publications: (PMID: 28330790) -
Inborn genetic diseases Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at