rs113994111

Positions:

• chr13-110174463-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001845.6(COL4A1):​c.3389G>A​(p.Gly1130Asp) variant causes a missense change. 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: 32)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 7.06

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL4A1. . Gene score misZ 3.0194 (greater than the threshold 3.09). Trascript score misZ 4.972 (greater than threshold 3.09). GenCC has associacion of gene with brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 13-110174463-C-T is Pathogenic according to our data. Variant chr13-110174463-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17416.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr13-110174463-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3389G>A	p.Gly1130Asp	missense_variant	39/52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3389G>A	p.Gly1130Asp	missense_variant	39/52	1	NM_001845.6	ENSP00000364979	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.6	H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.93		Gain of relative solvent accessibility (P = 0.0082);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.39
gMVP		1.0

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: rs113994111; hg19: chr13-110826810;