rs7990009

Variant names:

• chr13-110307341-C-G
• rs7990009
• NM_001846.4:c.-232C>G

Your query was ambiguous. Multiple possible variants found:

• chr13-110307341-C-G
• chr13-110307341-C-T

Variant summary

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

The NM_001846.4(COL4A2):​c.-232C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 293,478 control chromosomes in the GnomAD database, including 14,138 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7473 hom., cov: 33)
  • Exomes 𝑓: 0.30 (6665 hom.)
• Consequence: COL4A2 NM_001846.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.145
• Publications: 5 publications found

Genes affected

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]

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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-110307341-C-G is Benign according to our data. Variant chr13-110307341-C-G is described in ClinVar as Benign. ClinVar VariationId is 311090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.33 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.-232C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 48	NP_001837.2
	COL4A2	NM_001846.4	MANE Select	c.-232C>G		5_prime_UTR	Exon 1 of 48	NP_001837.2
	COL4A1	NM_001845.6	MANE Select	c.-314G>C		upstream_gene	N/A	NP_001836.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.-232C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 48	ENSP00000353654.5
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.-232C>G		5_prime_UTR	Exon 1 of 48	ENSP00000353654.5
	COL4A2	ENST00000714399.1		c.-232C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 49	ENSP00000519666.1

Frequencies

GnomAD3 genomes AF: 0.310 AC: 47078 AN: 151682 Hom.: 7450 Cov.: 33

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.370

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.262

GnomAD4 exome AF: 0.300 AC: 42513 AN: 141688 Hom.: 6665 Cov.: 0 AF XY: 0.301 AC XY: 21514 AN XY: 71366

African (AFR) AF: 0.327 AC: 1351 AN: 4130

American (AMR) AF: 0.364 AC: 1316 AN: 3620

Ashkenazi Jewish (ASJ) AF: 0.190 AC: 966 AN: 5078

East Asian (EAS) AF: 0.301 AC: 3523 AN: 11686

South Asian (SAS) AF: 0.348 AC: 1031 AN: 2962

European-Finnish (FIN) AF: 0.379 AC: 4469 AN: 11796

Middle Eastern (MID) AF: 0.177 AC: 138 AN: 780

European-Non Finnish (NFE) AF: 0.292 AC: 26881 AN: 91984

Other (OTH) AF: 0.294 AC: 2838 AN: 9652

GnomAD4 genome AF: 0.311 AC: 47140 AN: 151790 Hom.: 7473 Cov.: 33 AF XY: 0.314 AC XY: 23299 AN XY: 74166

African (AFR) AF: 0.331 AC: 13717 AN: 41440

American (AMR) AF: 0.337 AC: 5152 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.201 AC: 697 AN: 3468

East Asian (EAS) AF: 0.256 AC: 1300 AN: 5076

South Asian (SAS) AF: 0.323 AC: 1555 AN: 4820

European-Finnish (FIN) AF: 0.370 AC: 3901 AN: 10554

Middle Eastern (MID) AF: 0.188 AC: 55 AN: 292

European-Non Finnish (NFE) AF: 0.292 AC: 19817 AN: 67846

Other (OTH) AF: 0.266 AC: 561 AN: 2106

Alfa AF: 0.205 Hom.: 511

Bravo AF: 0.307

Asia WGS AF: 0.298 AC: 1028 AN: 3446

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.6
DANN	Benign	0.63
PhyloP100		0.14
PromoterAI		0.12	Neutral
Mutation Taster		=294/6	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: rs7990009; hg19: chr13-110959688; COSMIC: COSV64625842; COSMIC: COSV64625842;