rs7991332

Variant names:

• chr13-110307370-T-C
• rs7991332
• ENST00000360467:c.-203T>C

Your query was ambiguous. Multiple possible variants found:

• chr13-110307370-T-C
• chr13-110307370-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.-203T>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 0.305 in 242,402 control chromosomes in the GnomAD database, including 11,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7365 hom., cov: 32)
  • Exomes 𝑓: 0.30 (4106 hom.)
• Consequence: COL4A2 NM_001846.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.182

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-110307370-T-C is Benign according to our data. Variant chr13-110307370-T-C is described in ClinVar as [Benign]. Clinvar id is 311092.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.329 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.-203T>C		5_prime_UTR_variant	Exon 1 of 48	ENST00000360467.7	NP_001837.2
COL4A1	NM_001845.6	c.-343A>G		upstream_gene_variant		ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.-343A>G		upstream_gene_variant			NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467	c.-203T>C		5_prime_UTR_variant	Exon 1 of 48	5	NM_001846.4	ENSP00000353654.5
COL4A1	ENST00000375820.10	c.-343A>G		upstream_gene_variant		1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46672 AN: 151508 Hom.: 7343 Cov.: 32

Gnomad AFR AF: 0.324

Gnomad AMI AF: 0.423

Gnomad AMR AF: 0.335

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.322

Gnomad FIN AF: 0.371

Gnomad MID AF: 0.188

Gnomad NFE AF: 0.292

Gnomad OTH AF: 0.261

GnomAD4 exome AF: 0.299 AC: 27139 AN: 90786 Hom.: 4106 Cov.: 0 AF XY: 0.302 AC XY: 13753 AN XY: 45492

Gnomad4 AFR exome AF: 0.313

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.192

Gnomad4 EAS exome AF: 0.303

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.377

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.293

GnomAD4 genome AF: 0.308 AC: 46733 AN: 151616 Hom.: 7365 Cov.: 32 AF XY: 0.312 AC XY: 23104 AN XY: 74082

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.337

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.251

Gnomad4 SAS AF: 0.323

Gnomad4 FIN AF: 0.371

Gnomad4 NFE AF: 0.292

Gnomad4 OTH AF: 0.265

Alfa AF: 0.218 Hom.: 654

Bravo AF: 0.304

Asia WGS AF: 0.290 AC: 1002 AN: 3446

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brain small vessel disease 1 with or without ocular anomalies Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Porencephalic cyst Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Porencephaly 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	13
DANN	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs7991332; hg19: chr13-110959717; COSMIC: COSV64625850; COSMIC: COSV64625850;