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

Genomes: not found (cov: 23)

Consequence

COL4A5
NM_033380.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.20
Variant links:
Genes affected
COL4A5 (HGNC:2207): (collagen type IV alpha 5 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. Mutations in this gene are associated with X-linked Alport syndrome, also known as hereditary nephritis. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Aug 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_033380.3.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
Variant X-108624275-TGCCTGGAGACCCAGGGCA-T is Pathogenic according to our data. Variant chrX-108624275-TGCCTGGAGACCCAGGGCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL4A5NM_033380.3 linkc.2958_2975delGCCTGGAGACCCAGGGCA p.Pro987_Gln992del disruptive_inframe_deletion Exon 34 of 53 ENST00000328300.11 NP_203699.1 P29400-2Q49AM6A7MBN3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL4A5ENST00000328300.11 linkc.2958_2975delGCCTGGAGACCCAGGGCA p.Pro987_Gln992del disruptive_inframe_deletion Exon 34 of 53 1 NM_033380.3 ENSP00000331902.7 P29400-2
COL4A5ENST00000483338.1 linkc.1782_1799delGCCTGGAGACCCAGGGCA p.Pro595_Gln600del disruptive_inframe_deletion Exon 18 of 20 1 ENSP00000495685.1 Q49AM6
COL4A5ENST00000361603.7 linkc.2958_2975delGCCTGGAGACCCAGGGCA p.Pro987_Gln992del disruptive_inframe_deletion Exon 34 of 51 2 ENSP00000354505.2 P29400-1
COL4A5ENST00000505728.1 linkc.189_206delGCCTGGAGACCCAGGGCA p.Pro64_Gln69del disruptive_inframe_deletion Exon 2 of 5 3 ENSP00000424137.1 H0Y9H0

Frequencies

GnomAD3 genomes
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Jul 04, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Sep 16, 2022
GeneDx
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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
Dec 26, 2014
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1556421106; hg19: chrX-107867505; API