rs281865426

chr13-110187292-CC-AA

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PM5 PP2 PP5

The NM_001845.6(COL4A1):c.1573_1574delinsTT(p.Gly525Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G525R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.19

Genes affected

COL4A1 (HGNC:2202): (collagen type IV alpha 1 chain) This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_001845.6 (COL4A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001845.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-110187293-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2576606.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, COL4A1
• PP5: Variant 13-110187292-CC-AA is Pathogenic according to our data. Variant chr13-110187292-CC-AA is described in ClinVar as [Pathogenic]. Clinvar id is 18464.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.1573_1574delinsTT	p.Gly525Leu	missense_variant	25/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.1573_1574delinsTT	p.Gly525Leu	missense_variant	25/52	1	NM_001845.6	P1
COL4A1	ENST00000649738.1	n.1703_1704delinsTT		non_coding_transcript_exon_variant	25/31

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2010

- -

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: rs281865426; hg19: chr13-110839639;