rs113994103

Positions:

• chr13-110307027-T-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001845.6(COL4A1):​c.1A>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL4A1 NM_001845.6 start_lost
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 0.591

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 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-110307027-T-A is Pathogenic according to our data. Variant chr13-110307027-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 17415.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1A>T	p.Met1?	start_lost	1/52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1A>T	p.Met1?	start_lost	1/25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1A>T	p.Met1?	start_lost	1/52	1	NM_001845.6	ENSP00000364979	P1
COL4A1	ENST00000543140.6	c.1A>T	p.Met1?	start_lost	1/25	1		ENSP00000443348
COL4A2	ENST00000400163.7	c.-44-833T>A		intron_variant		5		ENSP00000383027
COL4A1	ENST00000649738.1	n.131A>T		non_coding_transcript_exon_variant	1/31

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Brain small vessel disease 1 with or without ocular anomalies Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	21
DANN	Benign	0.78
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.070
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.51	D
MutationTaster	Benign	1.0	A;A;A
PROVEAN	Benign	-0.49	N;N
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	1.0	T;T
Polyphen		0.17	B;.
Vest4		0.92
MutPred		0.96		Gain of catalytic residue at G2 (P = 0.0244);Gain of catalytic residue at G2 (P = 0.0244);
MVP		0.99
ClinPred		0.71	D
GERP RS		3.4
Varity_R		0.34
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs113994103; hg19: chr13-110959374;