rs16975492

Positions:

chr13-110181355-C-T

Variant summary

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

The NM_001845.6(COL4A1):c.2130G>A(p.Pro710Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,612,120 control chromosomes in the GnomAD database, including 103,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8380 hom., cov: 31)

Exomes 𝑓: 0.36 ( 95125 hom. )

Consequence

COL4A1
NM_001845.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.01

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:

COL4A1 (HGNC:):

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=-0.87).

BP6

Variant 13-110181355-C-T is Benign according to our data. Variant chr13-110181355-C-T is described in ClinVar as [Benign]. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.363 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.2130G>A	p.Pro710Pro	synonymous_variant	29/52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 linkuse as main transcript	c.2130G>A	p.Pro710Pro	synonymous_variant	29/52	1	NM_001845.6	ENSP00000364979.4		P02462-1
COL4A1	ENST00000649738.1 linkuse as main transcript	n.2260G>A		non_coding_transcript_exon_variant	29/31

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49626

AN:

151264

Hom.:

8368

Cov.:

show subpopulations

Gnomad AFR

AF:

0.239

Gnomad AMI

AF:

0.558

Gnomad AMR

AF:

0.357

Gnomad ASJ

AF:

0.343

Gnomad EAS

AF:

0.293

Gnomad SAS

AF:

0.369

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.343

GnomAD3 exomes

AF:

0.351

AC:

87621

AN:

249938

Hom.:

15747

AF XY:

0.352

AC XY:

47635

AN XY:

135146

show subpopulations

Gnomad AFR exome

AF:

0.241

Gnomad AMR exome

AF:

0.390

Gnomad ASJ exome

AF:

0.316

Gnomad EAS exome

AF:

0.293

Gnomad SAS exome

AF:

0.377

Gnomad FIN exome

AF:

0.351

Gnomad NFE exome

AF:

0.360

Gnomad OTH exome

AF:

0.344

GnomAD4 exome

AF:

0.359

AC:

523824

AN:

1460740

Hom.:

95125

Cov.:

AF XY:

0.359

AC XY:

261125

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.232

Gnomad4 AMR exome

AF:

0.388

Gnomad4 ASJ exome

AF:

0.320

Gnomad4 EAS exome

AF:

0.257

Gnomad4 SAS exome

AF:

0.373

Gnomad4 FIN exome

AF:

0.356

Gnomad4 NFE exome

AF:

0.366

Gnomad4 OTH exome

AF:

0.349

GnomAD4 genome

AF:

0.328

AC:

49665

AN:

151380

Hom.:

8380

Cov.:

AF XY:

0.329

AC XY:

24300

AN XY:

73876

show subpopulations

Gnomad4 AFR

AF:

0.239

Gnomad4 AMR

AF:

0.356

Gnomad4 ASJ

AF:

0.343

Gnomad4 EAS

AF:

0.293

Gnomad4 SAS

AF:

0.371

Gnomad4 FIN

AF:

0.353

Gnomad4 NFE

AF:

0.367

Gnomad4 OTH

AF:

0.349

Alfa

AF:

0.348

Hom.:

10498

Bravo

AF:

0.324

Asia WGS

AF:

0.354

AC:

1230

AN:

3478

EpiCase

AF:

0.353

EpiControl

AF:

0.353

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 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, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided

Benign:2

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

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

-0.87

CADD

Benign

0.74

DANN

Benign

0.41

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