rs7989823

Variant names:

• chr13-110307296-A-C
• rs7989823
• NM_001846.4:c.-277A>C

Your query was ambiguous. Multiple possible variants found:

• chr13-110307296-A-C
• chr13-110307296-A-G
• chr13-110307296-A-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.-277A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.613 in 371,128 control chromosomes in the GnomAD database, including 70,063 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (30465 hom., cov: 33)
  • Exomes 𝑓: 0.60 (39598 hom.)
• Consequence: COL4A2 NM_001846.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.92
• Publications: 16 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: Ambry Genetics, Orphanet, G2P, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet
• 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=-0.93).
• BP6: Variant 13-110307296-A-C is Benign according to our data. Variant chr13-110307296-A-C is described in ClinVar as Benign. ClinVar VariationId is 311089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.693 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.-277A>C		5_prime_UTR	Exon 1 of 48	NP_001837.2	P08572
	COL4A1	NM_001845.6	MANE Select	c.-269T>G		upstream_gene	N/A	NP_001836.3	P02462-1
	COL4A1	NM_001303110.2		c.-269T>G		upstream_gene	N/A	NP_001290039.1	P02462-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.-277A>C		5_prime_UTR	Exon 1 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.-277A>C		5_prime_UTR	Exon 1 of 49	ENSP00000519666.1	A0AAQ5BHW7
	COL4A2	ENST00000907571.1		c.-277A>C		5_prime_UTR	Exon 1 of 48	ENSP00000577630.1

Frequencies

GnomAD3 genomes AF: 0.631 AC: 95586 AN: 151560 Hom.: 30414 Cov.: 33

Gnomad AFR AF: 0.700

Gnomad AMI AF: 0.653

Gnomad AMR AF: 0.679

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.562

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.623

GnomAD4 exome AF: 0.600 AC: 131757 AN: 219460 Hom.: 39598 Cov.: 1 AF XY: 0.601 AC XY: 67483 AN XY: 112256

African (AFR) AF: 0.702 AC: 3769 AN: 5370

American (AMR) AF: 0.700 AC: 3783 AN: 5406

Ashkenazi Jewish (ASJ) AF: 0.597 AC: 4444 AN: 7440

East Asian (EAS) AF: 0.617 AC: 10614 AN: 17198

South Asian (SAS) AF: 0.620 AC: 5656 AN: 9126

European-Finnish (FIN) AF: 0.617 AC: 11526 AN: 18694

Middle Eastern (MID) AF: 0.609 AC: 643 AN: 1056

European-Non Finnish (NFE) AF: 0.587 AC: 82888 AN: 141102

Other (OTH) AF: 0.600 AC: 8434 AN: 14068

GnomAD4 genome AF: 0.631 AC: 95693 AN: 151668 Hom.: 30465 Cov.: 33 AF XY: 0.634 AC XY: 47006 AN XY: 74122

African (AFR) AF: 0.700 AC: 28977 AN: 41408

American (AMR) AF: 0.680 AC: 10381 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2117 AN: 3468

East Asian (EAS) AF: 0.563 AC: 2850 AN: 5060

South Asian (SAS) AF: 0.599 AC: 2886 AN: 4816

European-Finnish (FIN) AF: 0.626 AC: 6589 AN: 10526

Middle Eastern (MID) AF: 0.647 AC: 189 AN: 292

European-Non Finnish (NFE) AF: 0.587 AC: 39799 AN: 67818

Other (OTH) AF: 0.624 AC: 1311 AN: 2102

Alfa AF: 0.514 Hom.: 1488

Bravo AF: 0.636

Asia WGS AF: 0.557 AC: 1913 AN: 3430

ClinVar

ClinVar submissions

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	-0.93
CADD	Benign	3.4
DANN	Benign	0.42
PhyloP100		-1.9
PromoterAI		-0.019	Neutral
Mutation Taster		=295/5	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: rs7989823; hg19: chr13-110959643;