rs9588116

Positions:

• chr13-110206722-G-C
• chr13-110206722-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.808-7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,612,834 control chromosomes in the GnomAD database, including 107,411 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (11794 hom., cov: 32)
  • Exomes 𝑓: 0.36 (95617 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001471
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.775

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-110206722-G-C is Benign according to our data. Variant chr13-110206722-G-C is described in ClinVar as [Benign]. Clinvar id is 258263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110206722-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.808-7C>G		splice_region_variant, intron_variant		ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.808-7C>G		splice_region_variant, intron_variant			NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.808-7C>G		splice_region_variant, intron_variant		1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58711 AN: 151782 Hom.: 11765 Cov.: 32

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.447

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.300

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.355

GnomAD3 exomes AF: 0.370 AC: 92962 AN: 251358 Hom.: 18182 AF XY: 0.361 AC XY: 49070 AN XY: 135890

Gnomad AFR exome AF: 0.461

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.238

Gnomad SAS exome AF: 0.311

Gnomad FIN exome AF: 0.393

Gnomad NFE exome AF: 0.358

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.358 AC: 523198 AN: 1460936 Hom.: 95617 Cov.: 37 AF XY: 0.356 AC XY: 258613 AN XY: 726868

Gnomad4 AFR exome AF: 0.462

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.392

Gnomad4 NFE exome AF: 0.358

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.387 AC: 58799 AN: 151898 Hom.: 11794 Cov.: 32 AF XY: 0.387 AC XY: 28728 AN XY: 74244

Gnomad4 AFR AF: 0.448

Gnomad4 AMR AF: 0.448

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.359

Alfa AF: 0.280 Hom.: 1040

Bravo AF: 0.404

EpiCase AF: 0.343

EpiControl AF: 0.340

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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	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. -

Brain small vessel disease 1 with or without ocular anomalies Benign:3

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	Athena Diagnostics	Jun 01, 2017	- -
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 04, 2025	- -

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	-0.86
CADD	Benign	0.37
DANN	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0080
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: rs9588116; hg19: chr13-110859069; COSMIC: COSV65429672;