13-110307009-C-G

Variant names:

• chr13-110307009-C-G
• rs9515185
• NM_001845.6:c.19G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.19G>C​(p.Val7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,473,912 control chromosomes in the GnomAD database, including 126,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (11147 hom., cov: 34)
  • Exomes 𝑓: 0.41 (115178 hom.)
• Consequence: COL4A1 NM_001845.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.0290
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.4492954E-5).
• BP6: Variant 13-110307009-C-G is Benign according to our data. Variant chr13-110307009-C-G is described in ClinVar as Benign. ClinVar VariationId is 193216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

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.19G>C	p.Val7Leu	missense	Exon 1 of 52	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.19G>C	p.Val7Leu	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.19G>C	p.Val7Leu	missense	Exon 1 of 52	ENSP00000364979.4	P02462-1
	COL4A1	ENST00000543140.6	TSL:1	c.19G>C	p.Val7Leu	missense	Exon 1 of 25	ENSP00000443348.1	P02462-2
	COL4A1	ENST00000650424.2		c.19G>C	p.Val7Leu	missense	Exon 1 of 52	ENSP00000497477.2	A0A3B3ISV3

Frequencies

GnomAD3 genomes AF: 0.372 AC: 56421 AN: 151854 Hom.: 11156 Cov.: 34

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.628

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.413

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.435 AC: 36477 AN: 83772 AF XY: 0.440

Gnomad AFR exome AF: 0.255

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.553

Gnomad EAS exome AF: 0.631

Gnomad FIN exome AF: 0.284

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.413 AC: 546481 AN: 1321950 Hom.: 115178 Cov.: 40 AF XY: 0.416 AC XY: 270622 AN XY: 651288

African (AFR) AF: 0.242 AC: 6491 AN: 26814

American (AMR) AF: 0.403 AC: 11296 AN: 28014

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 13008 AN: 23322

East Asian (EAS) AF: 0.601 AC: 17666 AN: 29398

South Asian (SAS) AF: 0.462 AC: 33614 AN: 72698

European-Finnish (FIN) AF: 0.285 AC: 9334 AN: 32766

Middle Eastern (MID) AF: 0.544 AC: 2136 AN: 3928

European-Non Finnish (NFE) AF: 0.409 AC: 429429 AN: 1050156

Other (OTH) AF: 0.429 AC: 23507 AN: 54854

GnomAD4 genome AF: 0.371 AC: 56406 AN: 151962 Hom.: 11147 Cov.: 34 AF XY: 0.372 AC XY: 27620 AN XY: 74272

African (AFR) AF: 0.253 AC: 10514 AN: 41500

American (AMR) AF: 0.406 AC: 6198 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1856 AN: 3472

East Asian (EAS) AF: 0.628 AC: 3187 AN: 5076

South Asian (SAS) AF: 0.474 AC: 2288 AN: 4830

European-Finnish (FIN) AF: 0.280 AC: 2967 AN: 10578

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.413 AC: 28023 AN: 67908

Other (OTH) AF: 0.424 AC: 895 AN: 2110

Alfa AF: 0.380 Hom.: 1412

Bravo AF: 0.379

TwinsUK AF: 0.402 AC: 1489

ALSPAC AF: 0.407 AC: 1569

ExAC AF: 0.340 AC: 7121

Asia WGS AF: 0.500 AC: 1729 AN: 3466

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Brain small vessel disease 1 with or without ocular anomalies (3)
-	-	2	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (2)
-	-	2	not provided (2)
-	-	1	Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Benign	0.64
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.38	T
MetaRNN	Benign	0.000034	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PhyloP100		-0.029
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.29
Sift	Benign	0.57	T
Sift4G	Benign	0.98	T
Polyphen		0.0010	B
Vest4		0.040
MPC		0.38
ClinPred		0.0022	T
GERP RS		1.5
PromoterAI		0.027	Neutral
Varity_R		0.026
gMVP		0.40
Mutation Taster		=97/3	polymorphism (auto)

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: rs9515185; hg19: chr13-110959356; COSMIC: COSV64624437; COSMIC: COSV64624437;