rs267606743

Variant names:

• chr13-110192222-C-T
• rs267606743
• NM_001845.6:c.1528G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001845.6(COL4A1):​c.1528G>A​(p.Gly510Arg) 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: 33)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 5.80
• Publications: 6 publications found

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]

COL4A1 Gene-Disease associations (from GenCC):

• brain small vessel disease 1 with or without ocular anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontine autosomal dominant microangiopathy with leukoencephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal arterial tortuosity

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 13-110192222-C-T is Pathogenic according to our data. Variant chr13-110192222-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 18463.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1528G>A	p.Gly510Arg	missense_variant	Exon 24 of 52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1528G>A	p.Gly510Arg	missense_variant	Exon 24 of 25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1528G>A	p.Gly510Arg	missense_variant	Exon 24 of 52	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Retinal arterial tortuosity Pathogenic:1

Nov 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Nov 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.1	H;H
PhyloP100		5.8
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.88		Gain of catalytic residue at Q515 (P = 0.0117);Gain of catalytic residue at Q515 (P = 0.0117);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.93
gMVP		1.0
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs267606743; hg19: chr13-110844569;