rs2275843

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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:10

Conservation

PhyloP100: -3.68

Variant links:

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]

COL4A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.4640+7C>T		splice_region_variant, intron_variant	Intron 49 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL4A1	ENST00000375820.10 link	c.4640+7C>T	splice_region_variant, intron_variant	Intron 49 of 51	1	NM_001845.6	ENSP00000364979.4	P02462-1
COL4A1	ENST00000650424.1 link	c.794+7C>T	splice_region_variant, intron_variant	Intron 7 of 9			ENSP00000497477.2	A0A3B3ISV3
COL4A1	ENST00000467182.1 link	n.426C>T	non_coding_transcript_exon_variant	Exon 3 of 3	3
COL4A1	ENST00000649720.1 link	n.808+7C>T	splice_region_variant, intron_variant	Intron 4 of 6

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23209

AN:

151970

Hom.:

1875

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.162

AC XY:

117404

AN XY:

726296

show subpopulations

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.:

AF XY:

0.154

AC XY:

11431

AN XY:

74354

show subpopulations

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Jun 01, 2017

Athena Diagnostics

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

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:1

Jan 12, 2018

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

-0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over