rs9515185

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001845.6(COL4A1):c.19G>C(p.Val7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.409 in 1,473,912 control chromosomes in the GnomAD database, including 126,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 11147 hom., cov: 34)

Exomes 𝑓: 0.41 ( 115178 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.0290

Variant links:

Genes affected

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 links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the COL4A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 194 curated pathogenic missense variants (we use a threshold of 10). The gene has 77 curated benign missense variants. Gene score misZ: 3.0194 (below the threshold of 3.09). Trascript score misZ: 4.972 (above the threshold of 3.09). GenCC associations: The gene is linked to brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.

BP4

Computational evidence support a benign effect (MetaRNN=3.4492954E-5).

BP6

Variant 13-110307009-C-G is Benign according to our data. Variant chr13-110307009-C-G is described in ClinVar as [Benign]. Clinvar id is 193216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110307009-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.61 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.19G>C	p.Val7Leu	missense_variant	Exon 1 of 52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.19G>C	p.Val7Leu	missense_variant	Exon 1 of 25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.19G>C	p.Val7Leu	missense_variant	Exon 1 of 52	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.372

AC:

56421

AN:

151854

Hom.:

11156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.253

Gnomad AMI

AF:

0.357

Gnomad AMR

AF:

0.406

Gnomad ASJ

AF:

0.535

Gnomad EAS

AF:

0.628

Gnomad SAS

AF:

0.475

Gnomad FIN

AF:

0.280

Gnomad MID

AF:

0.525

Gnomad NFE

AF:

0.413

Gnomad OTH

AF:

0.429

GnomAD3 exomes

AF:

0.435

AC:

36477

AN:

83772

Hom.:

8340

AF XY:

0.440

AC XY:

20975

AN XY:

47692

show subpopulations

Gnomad AFR exome

AF:

0.255

Gnomad AMR exome

AF:

0.393

Gnomad ASJ exome

AF:

0.553

Gnomad EAS exome

AF:

0.631

Gnomad SAS exome

AF:

0.466

Gnomad FIN exome

AF:

0.284

Gnomad NFE exome

AF:

0.417

Gnomad OTH exome

AF:

0.469

GnomAD4 exome

AF:

0.413

AC:

546481

AN:

1321950

Hom.:

115178

Cov.:

AF XY:

0.416

AC XY:

270622

AN XY:

651288

show subpopulations

Gnomad4 AFR exome

AF:

0.242

Gnomad4 AMR exome

AF:

0.403

Gnomad4 ASJ exome

AF:

0.558

Gnomad4 EAS exome

AF:

0.601

Gnomad4 SAS exome

AF:

0.462

Gnomad4 FIN exome

AF:

0.285

Gnomad4 NFE exome

AF:

0.409

Gnomad4 OTH exome

AF:

0.429

GnomAD4 genome

AF:

0.371

AC:

56406

AN:

151962

Hom.:

11147

Cov.:

AF XY:

0.372

AC XY:

27620

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.253

Gnomad4 AMR

AF:

0.406

Gnomad4 ASJ

AF:

0.535

Gnomad4 EAS

AF:

0.628

Gnomad4 SAS

AF:

0.474

Gnomad4 FIN

AF:

0.280

Gnomad4 NFE

AF:

0.413

Gnomad4 OTH

AF:

0.424

Alfa

AF:

0.380

Hom.:

1412

Bravo

AF:

0.379

TwinsUK

AF:

0.402

AC:

1489

ALSPAC

AF:

0.407

AC:

1569

ExAC

AF:

0.340

AC:

7121

Asia WGS

AF:

0.500

AC:

1729

AN:

3466

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 23, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:3

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Porencephalic cyst

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

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.38

T;T

MetaRNN

Benign

0.000034

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.34

N;N

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

0.090

N;N

REVEL

Uncertain

0.29

Sift

Benign

0.57

T;T

Sift4G

Benign

0.98

T;T

Polyphen

0.0010

B;.

Vest4

0.040

MPC

0.38

ClinPred

0.0022

GERP RS

1.5

Varity_R

0.026

gMVP

0.40

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over