rs874203

Positions:

• chr13-110175227-T-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):​c.3189A>T​(p.Arg1063=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,613,290 control chromosomes in the GnomAD database, including 105,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (8757 hom., cov: 33)
  • Exomes 𝑓: 0.36 (96789 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.671

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 13-110175227-T-A is Benign according to our data. Variant chr13-110175227-T-A is described in ClinVar as [Benign]. Clinvar id is 258251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110175227-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.671 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3189A>T	p.Arg1063=	synonymous_variant	37/52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3189A>T	p.Arg1063=	synonymous_variant	37/52	1	NM_001845.6	ENSP00000364979	P1

Frequencies

GnomAD3 genomes AF: 0.339 AC: 51446 AN: 151810 Hom.: 8743 Cov.: 33

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.361

Gnomad ASJ AF: 0.340

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.351

GnomAD3 exomes AF: 0.354 AC: 88877 AN: 251100 Hom.: 15974 AF XY: 0.355 AC XY: 48167 AN XY: 135740

Gnomad AFR exome AF: 0.278

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.367

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.362 AC: 528802 AN: 1461362 Hom.: 96789 Cov.: 47 AF XY: 0.362 AC XY: 263210 AN XY: 727022

Gnomad4 AFR exome AF: 0.268

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.318

Gnomad4 EAS exome AF: 0.265

Gnomad4 SAS exome AF: 0.365

Gnomad4 FIN exome AF: 0.356

Gnomad4 NFE exome AF: 0.369

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.339 AC: 51498 AN: 151928 Hom.: 8757 Cov.: 33 AF XY: 0.339 AC XY: 25173 AN XY: 74250

Gnomad4 AFR AF: 0.276

Gnomad4 AMR AF: 0.361

Gnomad4 ASJ AF: 0.340

Gnomad4 EAS AF: 0.295

Gnomad4 SAS AF: 0.361

Gnomad4 FIN AF: 0.351

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.356

Alfa AF: 0.352 Hom.: 3195

Bravo AF: 0.337

Asia WGS AF: 0.355 AC: 1234 AN: 3478

EpiCase AF: 0.355

EpiControl AF: 0.352

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	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: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	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 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	-0.71
CADD	Benign	0.020
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

Other links and lift over

dbSNP: rs874203; hg19: chr13-110827574; COSMIC: COSV65421604;