rs2275843

Positions:

• chr13-110161185-G-A

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.4640+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,611,832 control chromosomes in the GnomAD database, including 21,864 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 0.15 (1874 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19990 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.00001050
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -3.68

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=-0.91).
• BP6: Variant 13-110161185-G-A is Benign according to our data. Variant chr13-110161185-G-A is described in ClinVar as [Benign]. Clinvar id is 258257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110161185-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.4640+7C>T		splice_region_variant, intron_variant		ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.4640+7C>T		splice_region_variant, intron_variant		1	NM_001845.6	P1
COL4A1	ENST00000650424.1	c.796+7C>T		splice_region_variant, intron_variant
COL4A1	ENST00000467182.1	n.426C>T		non_coding_transcript_exon_variant	3/3	3
COL4A1	ENST00000649720.1	n.808+7C>T		splice_region_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23209 AN: 151970 Hom.: 1875 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.193

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.186

GnomAD3 exomes AF: 0.167 AC: 41854 AN: 251118 Hom.: 3710 AF XY: 0.166 AC XY: 22568 AN XY: 135728

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.176

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.162 AC: 235921 AN: 1459744 Hom.: 19990 Cov.: 31 AF XY: 0.162 AC XY: 117404 AN XY: 726296

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.173

GnomAD4 genome AF: 0.153 AC: 23221 AN: 152088 Hom.: 1874 Cov.: 33 AF XY: 0.154 AC XY: 11431 AN XY: 74354

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.192

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.184

Alfa AF: 0.162 Hom.: 4123

Bravo AF: 0.157

Asia WGS AF: 0.263 AC: 912 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	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 12, 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	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Porencephalic cyst Benign:1

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 12, 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	-0.91
CADD	Benign	0.11
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000010
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.010		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: rs2275843; hg19: chr13-110813532; COSMIC: COSV65423062; COSMIC: COSV65423062;