rs589985

Positions:

• chr13-110167239-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.3877-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 1,601,826 control chromosomes in the GnomAD database, including 355,308 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31769 hom., cov: 31)
  • Exomes 𝑓: 0.67 (323539 hom.)
• Consequence: COL4A1 NM_001845.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001695
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.608

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=-0.9).
• BP6: Variant 13-110167239-G-A is Benign according to our data. Variant chr13-110167239-G-A is described in ClinVar as [Benign]. Clinvar id is 258253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110167239-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3877-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3877-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001845.6	ENSP00000364979	P1
COL4A1	ENST00000650424.1	c.33-9C>T		splice_polypyrimidine_tract_variant, intron_variant				ENSP00000497477

Frequencies

GnomAD3 genomes AF: 0.644 AC: 97688 AN: 151776 Hom.: 31752 Cov.: 31

Gnomad AFR AF: 0.565

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.696

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.637

GnomAD3 exomes AF: 0.680 AC: 170857 AN: 251100 Hom.: 58892 AF XY: 0.676 AC XY: 91810 AN XY: 135758

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.813

Gnomad ASJ exome AF: 0.620

Gnomad EAS exome AF: 0.648

Gnomad SAS exome AF: 0.674

Gnomad FIN exome AF: 0.740

Gnomad NFE exome AF: 0.660

Gnomad OTH exome AF: 0.654

GnomAD4 exome AF: 0.666 AC: 965364 AN: 1449932 Hom.: 323539 Cov.: 33 AF XY: 0.665 AC XY: 480392 AN XY: 721984

Gnomad4 AFR exome AF: 0.553

Gnomad4 AMR exome AF: 0.801

Gnomad4 ASJ exome AF: 0.621

Gnomad4 EAS exome AF: 0.677

Gnomad4 SAS exome AF: 0.677

Gnomad4 FIN exome AF: 0.735

Gnomad4 NFE exome AF: 0.660

Gnomad4 OTH exome AF: 0.664

GnomAD4 genome AF: 0.644 AC: 97748 AN: 151894 Hom.: 31769 Cov.: 31 AF XY: 0.648 AC XY: 48145 AN XY: 74246

Gnomad4 AFR AF: 0.564

Gnomad4 AMR AF: 0.720

Gnomad4 ASJ AF: 0.616

Gnomad4 EAS AF: 0.670

Gnomad4 SAS AF: 0.694

Gnomad4 FIN AF: 0.732

Gnomad4 NFE AF: 0.659

Gnomad4 OTH AF: 0.641

Alfa AF: 0.647 Hom.: 19110

Bravo AF: 0.641

Asia WGS AF: 0.706 AC: 2458 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	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	Athena Diagnostics	Jun 02, 2021	- -
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 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	Genome-Nilou Lab	Jul 22, 2021	- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Porencephalic cyst Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.24

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs589985; hg19: chr13-110819586;