rs16975492

chr13-110181355-C-T

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.2130G>A(p.Pro710=) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -5.01

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=-0.87).
• 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	UniProt
COL4A1	NM_001845.6	c.2130G>A	p.Pro710=	synonymous_variant	29/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.2130G>A	p.Pro710=	synonymous_variant	29/52	1	NM_001845.6	P1
COL4A1	ENST00000649738.1	n.2260G>A		non_coding_transcript_exon_variant	29/31

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49626 AN: 151264 Hom.: 8368 Cov.: 31

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

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.: 41 AF XY: 0.359 AC XY: 261125 AN XY: 726648

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.: 31 AF XY: 0.329 AC XY: 24300 AN XY: 73876

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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

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	- -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

Other links and lift over

dbSNP: rs16975492; hg19: chr13-110833702; COSMIC: COSV65427049;