rs7991332

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.182

Publications

4 publications found

Variant links:

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]

COL4A2 links:

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

COL4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4 link	c.-203T>C	5_prime_UTR_variant	Exon 1 of 48	ENST00000360467.7	NP_001837.2	P08572A0A024RDW8
COL4A1	NM_001845.6 link	c.-343A>G	upstream_gene_variant		ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.-343A>G	upstream_gene_variant			NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7 link	c.-203T>C		5_prime_UTR_variant	Exon 1 of 48	5	NM_001846.4	ENSP00000353654.5		P08572
COL4A1	ENST00000375820.10 link	c.-343A>G		upstream_gene_variant		1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.308

AC:

46672

AN:

151508

Hom.:

7343

Cov.:

show subpopulations

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.:

AF XY:

0.302

AC XY:

13753

AN XY:

45492

show subpopulations

African (AFR)

AF:

0.313

AC:

922

AN:

2948

American (AMR)

AF:

0.375

AC:

876

AN:

2336

Ashkenazi Jewish (ASJ)

AF:

0.192

AC:

659

AN:

3430

East Asian (EAS)

AF:

0.303

AC:

2192

AN:

7230

South Asian (SAS)

AF:

0.320

AC:

385

AN:

1202

European-Finnish (FIN)

AF:

0.377

AC:

2654

AN:

7042

Middle Eastern (MID)

AF:

0.185

AC:

100

AN:

540

European-Non Finnish (NFE)

AF:

0.293

AC:

17493

AN:

59716

Other (OTH)

AF:

0.293

AC:

1858

AN:

6342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

908

1816

2724

3632

4540

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.308

AC:

46733

AN:

151616

Hom.:

7365

Cov.:

AF XY:

0.312

AC XY:

23104

AN XY:

74082

show subpopulations

African (AFR)

AF:

0.323

AC:

13384

AN:

41396

American (AMR)

AF:

0.337

AC:

5141

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

695

AN:

3466

East Asian (EAS)

AF:

0.251

AC:

1268

AN:

5058

South Asian (SAS)

AF:

0.323

AC:

1557

AN:

4816

European-Finnish (FIN)

AF:

0.371

AC:

3902

AN:

10530

Middle Eastern (MID)

AF:

0.188

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.292

AC:

19789

AN:

67770

Other (OTH)

AF:

0.265

AC:

558

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1657

3314

4971

6628

8285

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

460

920

1380

1840

2300

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

LINK: link

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

- -

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. -

Porencephalic cyst

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Benign

0.52

PhyloP100

-0.18

PromoterAI

0.0078

Neutral

(source)

Mutation Taster

=289/11

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over