13-110198495-A-G

Position:

chr13-110198495-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The ENST00000375820.10(COL4A1):c.1257T>C(p.Pro419=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,613,652 control chromosomes in the GnomAD database, including 59,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 5286 hom., cov: 31)

Exomes 𝑓: 0.27 ( 54094 hom. )

Consequence

COL4A1
ENST00000375820.10 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -2.90

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 13-110198495-A-G is Benign according to our data. Variant chr13-110198495-A-G is described in ClinVar as [Benign]. Clinvar id is 258246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110198495-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.9 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6 linkuse as main transcript	c.1257T>C	p.Pro419=	synonymous_variant	21/52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 linkuse as main transcript	c.1257T>C	p.Pro419=	synonymous_variant	21/25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 linkuse as main transcript	c.1257T>C	p.Pro419=	synonymous_variant	21/52	1	NM_001845.6	ENSP00000364979	P1	P02462-1
COL4A1	ENST00000543140.6 linkuse as main transcript	c.1257T>C	p.Pro419=	synonymous_variant	21/25	1		ENSP00000443348		P02462-2
COL4A1	ENST00000647797.1 linkuse as main transcript	c.1137T>C	p.Pro379=	synonymous_variant	20/20			ENSP00000497756
COL4A1	ENST00000649738.1 linkuse as main transcript	n.1387T>C		non_coding_transcript_exon_variant	21/31

Frequencies

GnomAD3 genomes

AF:

0.256

AC:

38945

AN:

151882

Hom.:

5276

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.246

Gnomad EAS

AF:

0.0483

Gnomad SAS

AF:

0.210

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.241

Gnomad NFE

AF:

0.278

Gnomad OTH

AF:

0.231

GnomAD3 exomes

AF:

0.260

AC:

65165

AN:

250958

Hom.:

9285

AF XY:

0.256

AC XY:

34819

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.221

Gnomad AMR exome

AF:

0.332

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.0449

Gnomad SAS exome

AF:

0.224

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.276

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.267

AC:

389888

AN:

1461652

Hom.:

54094

Cov.:

AF XY:

0.266

AC XY:

193177

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.222

Gnomad4 AMR exome

AF:

0.336

Gnomad4 ASJ exome

AF:

0.241

Gnomad4 EAS exome

AF:

0.0367

Gnomad4 SAS exome

AF:

0.230

Gnomad4 FIN exome

AF:

0.327

Gnomad4 NFE exome

AF:

0.275

Gnomad4 OTH exome

AF:

0.250

GnomAD4 genome

AF:

0.257

AC:

38989

AN:

152000

Hom.:

5286

Cov.:

AF XY:

0.258

AC XY:

19204

AN XY:

74296

show subpopulations

Gnomad4 AFR

AF:

0.218

Gnomad4 AMR

AF:

0.319

Gnomad4 ASJ

AF:

0.246

Gnomad4 EAS

AF:

0.0481

Gnomad4 SAS

AF:

0.210

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.278

Gnomad4 OTH

AF:

0.228

Alfa

AF:

0.241

Hom.:

1540

Bravo

AF:

0.251

Asia WGS

AF:

0.131

AC:

458

AN:

3478

EpiCase

AF:

0.263

EpiControl

AF:

0.259

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2017	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.015

DANN

Benign

0.44

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