chr13-110306953-GGCCCGGCTGTGCTCCTCGTGGAGCAGAAGGGCGGCGGGCAGCAGCAGCAGCCAGACGCTGAGCCGGGGCCCCATGGTGGCGCGCCCGAGGCGGCGAGGGACGGCT-G

Position:

• chr13-110306953-GGCCCGGCTGTGCTCCTCGTGGAGCAGAAGGGCGGCGGGCAGCAGCAGCAGCCAGACGCTGAGCCGGGGCCCCATGGTGGCGCGCCCGAGGCGGCGAGGGACGGCT-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001845.6(COL4A1):​c.-31_74del variant causes a start lost, 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL4A1 NM_001845.6 start_lost, 5_prime_UTR
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.51

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]

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. 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. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-110306953-GGCCCGGCTGTGCTCCTCGTGGAGCAGAAGGGCGGCGGGCAGCAGCAGCAGCCAGACGCTGAGCCGGGGCCCCATGGTGGCGCGCCCGAGGCGGCGAGGGACGGCT-G is Pathogenic according to our data. Variant chr13-110306953-GGCCCGGCTGTGCTCCTCGTGGAGCAGAAGGGCGGCGGGCAGCAGCAGCAGCCAGACGCTGAGCCGGGGCCCCATGGTGGCGCGCCCGAGGCGGCGAGGGACGGCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 2741718.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.-31_74del		start_lost, 5_prime_UTR_variant	1/52	ENST00000375820.10
COL4A1	NM_001303110.2	c.-31_74del		start_lost, 5_prime_UTR_variant	1/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.-31_74del		start_lost, 5_prime_UTR_variant	1/52	1	NM_001845.6	P1
COL4A1	ENST00000543140.6	c.-31_74del		start_lost, 5_prime_UTR_variant	1/25	1
COL4A2	ENST00000400163.7	c.-44-899_-44-795del		intron_variant		5
COL4A1	ENST00000649738.1	n.100_204del		non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2023

This sequence change affects the initiator methionine of the COL4A1 mRNA. The next in-frame methionine is located at codon 65. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. This variant disrupts a region of the COL4A1 protein in which other variant(s) (p.Gly46Arg) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-110959300;