rs650724

chr13-110152462-G-Achr13-110152462-G-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.4800C>T(p.Ser1600=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,613,748 control chromosomes in the GnomAD database, including 9,606 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1600S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.13 (1605 hom., cov: 33)
  • Exomes 𝑓: 0.097 (8001 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.103

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=-0.58).
• BP6: Variant 13-110152462-G-A is Benign according to our data. Variant chr13-110152462-G-A is described in ClinVar as [Benign]. Clinvar id is 258260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110152462-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.4800C>T	p.Ser1600=	synonymous_variant	51/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.4800C>T	p.Ser1600=	synonymous_variant	51/52	1	NM_001845.6	P1
COL4A1	ENST00000650424.1	c.957C>T	p.Ser319=	synonymous_variant	9/10
COL4A1	ENST00000649720.1	n.968C>T		non_coding_transcript_exon_variant	6/7

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19848 AN: 152128 Hom.: 1593 Cov.: 33

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.0833

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.0942

Gnomad OTH AF: 0.131

GnomAD3 exomes AF: 0.113 AC: 28294 AN: 250762 Hom.: 2165 AF XY: 0.107 AC XY: 14448 AN XY: 135614

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.226

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.0775

Gnomad FIN exome AF: 0.0852

Gnomad NFE exome AF: 0.0966

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.0969 AC: 141563 AN: 1461502 Hom.: 8001 Cov.: 32 AF XY: 0.0956 AC XY: 69528 AN XY: 727052

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.224

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.00217

Gnomad4 SAS exome AF: 0.0775

Gnomad4 FIN exome AF: 0.0847

Gnomad4 NFE exome AF: 0.0928

Gnomad4 OTH exome AF: 0.0999

GnomAD4 genome AF: 0.131 AC: 19895 AN: 152246 Hom.: 1605 Cov.: 33 AF XY: 0.131 AC XY: 9723 AN XY: 74456

Gnomad4 AFR AF: 0.205

Gnomad4 AMR AF: 0.193

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.00443

Gnomad4 SAS AF: 0.0718

Gnomad4 FIN AF: 0.0833

Gnomad4 NFE AF: 0.0942

Gnomad4 OTH AF: 0.130

Alfa AF: 0.112 Hom.: 526

Bravo AF: 0.144

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.102

EpiControl AF: 0.105

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 09, 2016	- -
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	Athena Diagnostics	Jun 01, 2017	- -
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. -

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	-0.58
Cadd	Benign	3.1
Dann	Benign	0.47

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: rs650724; hg19: chr13-110804809; COSMIC: COSV65428107;