13-110307358-C-T

Variant names:

• chr13-110307358-C-T
• rs7990017
• NM_001846.4:c.-215C>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.-215C>T 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 0.49 in 260,090 control chromosomes in the GnomAD database, including 31,514 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18514 hom., cov: 32)
  • Exomes 𝑓: 0.49 (13000 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: -3.06
• 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: 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=-0.82).
• BP6: Variant 13-110307358-C-T is Benign according to our data. Variant chr13-110307358-C-T is described in ClinVar as Benign. ClinVar VariationId is 311091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.576 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.-215C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 48	NP_001837.2	P08572
	COL4A2	NM_001846.4	MANE Select	c.-215C>T		5_prime_UTR	Exon 1 of 48	NP_001837.2	P08572
	COL4A1	NM_001845.6	MANE Select	c.-331G>A		upstream_gene	N/A	NP_001836.3	P02462-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.-215C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.-215C>T		5_prime_UTR	Exon 1 of 48	ENSP00000353654.5	P08572
	COL4A2	ENST00000714399.1		c.-215C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 49	ENSP00000519666.1	A0AAQ5BHW7

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74481 AN: 151502 Hom.: 18486 Cov.: 32

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.532

Gnomad SAS AF: 0.529

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.529

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.488

GnomAD4 exome AF: 0.488 AC: 52921 AN: 108478 Hom.: 13000 Cov.: 0 AF XY: 0.492 AC XY: 26818 AN XY: 54536

African (AFR) AF: 0.472 AC: 1625 AN: 3442

American (AMR) AF: 0.620 AC: 1747 AN: 2820

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1873 AN: 4050

East Asian (EAS) AF: 0.584 AC: 5250 AN: 8990

South Asian (SAS) AF: 0.522 AC: 771 AN: 1476

European-Finnish (FIN) AF: 0.494 AC: 4291 AN: 8684

Middle Eastern (MID) AF: 0.468 AC: 292 AN: 624

European-Non Finnish (NFE) AF: 0.471 AC: 33414 AN: 70872

Other (OTH) AF: 0.486 AC: 3658 AN: 7520

GnomAD4 genome AF: 0.492 AC: 74557 AN: 151612 Hom.: 18514 Cov.: 32 AF XY: 0.496 AC XY: 36765 AN XY: 74056

African (AFR) AF: 0.478 AC: 19787 AN: 41368

American (AMR) AF: 0.586 AC: 8960 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1639 AN: 3472

East Asian (EAS) AF: 0.533 AC: 2681 AN: 5034

South Asian (SAS) AF: 0.531 AC: 2555 AN: 4814

European-Finnish (FIN) AF: 0.497 AC: 5235 AN: 10532

Middle Eastern (MID) AF: 0.524 AC: 151 AN: 288

European-Non Finnish (NFE) AF: 0.473 AC: 32052 AN: 67810

Other (OTH) AF: 0.490 AC: 1030 AN: 2104

Alfa AF: 0.476 Hom.: 2148

Bravo AF: 0.495

Asia WGS AF: 0.494 AC: 1699 AN: 3440

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	-0.82
CADD	Benign	2.4
DANN	Benign	0.80
PhyloP100		-3.1
PromoterAI		0.0045	Neutral
Mutation Taster		=287/13	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: rs7990017; hg19: chr13-110959705; COSMIC: COSV64625848; COSMIC: COSV64625848;