rs589985

Variant names:

• chr13-110167239-G-A
• rs589985
• NM_001845.6:c.3877-9C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.3877-9C>T variant causes a 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 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3877-9C>T		intron_variant	Intron 43 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3877-9C>T		intron_variant	Intron 43 of 51	1	NM_001845.6	ENSP00000364979.4

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

GnomAD2 exomes AF: 0.680 AC: 170857 AN: 251100 AF XY: 0.676

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 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

African (AFR) AF: 0.553 AC: 18382 AN: 33238

American (AMR) AF: 0.801 AC: 35816 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.621 AC: 16202 AN: 26082

East Asian (EAS) AF: 0.677 AC: 26801 AN: 39612

South Asian (SAS) AF: 0.677 AC: 58273 AN: 86046

European-Finnish (FIN) AF: 0.735 AC: 39236 AN: 53374

Middle Eastern (MID) AF: 0.616 AC: 3541 AN: 5748

European-Non Finnish (NFE) AF: 0.660 AC: 727293 AN: 1101128

Other (OTH) AF: 0.664 AC: 39820 AN: 59998

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

African (AFR) AF: 0.564 AC: 23347 AN: 41372

American (AMR) AF: 0.720 AC: 10997 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2136 AN: 3468

East Asian (EAS) AF: 0.670 AC: 3454 AN: 5158

South Asian (SAS) AF: 0.694 AC: 3334 AN: 4804

European-Finnish (FIN) AF: 0.732 AC: 7732 AN: 10558

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44788 AN: 67954

Other (OTH) AF: 0.641 AC: 1349 AN: 2106

Alfa AF: 0.646 Hom.: 19241

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

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 02, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 14, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Porencephalic cyst Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.3
DANN	Benign	0.24
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism (auto)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Other links and lift over

dbSNP: rs589985; hg19: chr13-110819586;