rs1556421106

chrX-108624275-TGCCTGGAGACCCAGGGCA-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM4 PP3 PP5_Very_Strong

The NM_033380.3(COL4A5):c.2958_2975del(p.Asp989_Gly994del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: COL4A5 NM_033380.3 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.20

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_033380.3
• 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/exons	MANE	UniProt
COL4A5	NM_033380.3	c.2958_2975del	p.Asp989_Gly994del	inframe_deletion	34/53	ENST00000328300.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A5	ENST00000328300.11	c.2958_2975del	p.Asp989_Gly994del	inframe_deletion	34/53	1	NM_033380.3
COL4A5	ENST00000483338.1	c.1782_1799del	p.Asp597_Gly602del	inframe_deletion	18/20	1
COL4A5	ENST00000361603.7	c.2958_2975del	p.Asp989_Gly994del	inframe_deletion	34/51	2		P1
COL4A5	ENST00000505728.1	c.191_208del	p.Asp67_Gly72del	inframe_deletion	2/5	3

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

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 04, 2021	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. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 10094548; Invitae). This variant is also known as 3161-3178del (del987-992). ClinVar contains an entry for this variant (Variation ID: 520604). 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). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 16, 2022	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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556421106; hg19: chrX-107867505;