13-110306954-G-C

Variant names:

• chr13-110306954-G-C
• rs1188718847
• NM_001845.6:c.74C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001845.6(COL4A1):​c.74C>G​(p.Ala25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000151 in 1,322,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A25A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.678
• Publications: 0 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]

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]

COL4A2 Gene-Disease associations (from GenCC):

• porencephaly 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• COL4A1 or COL4A2-related cerebral small vessel disease

  Inheritance: AD Classification: MODERATE Submitted by: Illumina
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20188242).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.74C>G	p.Ala25Gly	missense	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.74C>G	p.Ala25Gly	missense	Exon 1 of 25	NP_001290039.1	P02462-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.74C>G	p.Ala25Gly	missense	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.74C>G	p.Ala25Gly	missense	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.74C>G	p.Ala25Gly	missense	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 1 AN: 84302 AF XY: 0.0000209

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000151 AC: 2 AN: 1322156 Hom.: 0 Cov.: 30 AF XY: 0.00000307 AC XY: 2 AN XY: 651042

African (AFR) AF: 0.00 AC: 0 AN: 26912

American (AMR) AF: 0.00 AC: 0 AN: 28454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23414

East Asian (EAS) AF: 0.00 AC: 0 AN: 29144

South Asian (SAS) AF: 0.0000275 AC: 2 AN: 72734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32784

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4016

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1049780

Other (OTH) AF: 0.00 AC: 0 AN: 54918

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	Retinal arterial tortuosity;C2673195:Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;C3281105:Hemorrhage, intracerebral, susceptibility to;C4551998:Brain small vessel disease 1 with or without ocular anomalies;C5231411:Microangiopathy and leukoencephalopathy, pontine, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.68
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.25
Sift	Benign	0.34	T
Sift4G	Benign	0.33	T
Polyphen		0.49	P
Vest4		0.094
MutPred		0.46		Gain of catalytic residue at G30 (P = 0.001)
MVP		0.53
MPC		0.39
ClinPred		0.10	T
GERP RS		1.4
PromoterAI		-0.066	Neutral
Varity_R		0.035
gMVP		0.32
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs1188718847; hg19: chr13-110959301;