13-110152381-G-C

Variant names:

• chr13-110152381-G-C
• rs672601348
• NM_001845.6:c.4881C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_001845.6(COL4A1):​c.4881C>G​(p.Asn1627Lys) variant causes a missense 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 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.265

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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the COL4A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 194 curated pathogenic missense variants (we use a threshold of 10). The gene has 77 curated benign missense variants. Gene score misZ: 3.0194 (below the threshold of 3.09). Trascript score misZ: 4.972 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.904
• PP5: Variant 13-110152381-G-C is Pathogenic according to our data. Variant chr13-110152381-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 161976.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.4881C>G	p.Asn1627Lys	missense_variant	Exon 51 of 52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.4881C>G	p.Asn1627Lys	missense_variant	Exon 51 of 52	1	NM_001845.6	ENSP00000364979.4
COL4A1	ENST00000650424.1	c.1035C>G	p.Asn345Lys	missense_variant	Exon 9 of 10			ENSP00000497477.2
COL4A1	ENST00000649720.1	n.1049C>G		non_coding_transcript_exon_variant	Exon 6 of 7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

May 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	0.92
DANN	Benign	0.88
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.91
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.35	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.62
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.67		Gain of catalytic residue at N1627 (P = 0.0071);
MVP		0.84
MPC		0.44
ClinPred		0.72	D
GERP RS		-11
Varity_R		0.91
gMVP		0.89

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: rs672601348; hg19: chr13-110804728;