rs9521650

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.234+8C>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 0.15 in 1,613,246 control chromosomes in the GnomAD database, including 18,771 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 0.14 ( 1564 hom., cov: 31)

Exomes 𝑓: 0.15 ( 17207 hom. )

Consequence

COL4A1
NM_001845.6 splice_region, intron

Scores

Splicing: ADA: 0.00002697

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -1.56

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=-0.92).

BP6

Variant 13-110213918-G-A is Benign according to our data. Variant chr13-110213918-G-A is described in ClinVar as [Benign]. Clinvar id is 196328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110213918-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.234+8C>T		splice_region_variant, intron_variant	Intron 3 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.234+8C>T		splice_region_variant, intron_variant	Intron 3 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.234+8C>T		splice_region_variant, intron_variant	Intron 3 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.138

AC:

20943

AN:

151752

Hom.:

1563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0931

Gnomad AMI

AF:

0.400

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.232

Gnomad SAS

AF:

0.0898

Gnomad FIN

AF:

0.137

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.158

Gnomad OTH

AF:

0.159

GnomAD3 exomes

AF:

0.141

AC:

35523

AN:

251490

Hom.:

2785

AF XY:

0.142

AC XY:

19365

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.0882

Gnomad AMR exome

AF:

0.0969

Gnomad ASJ exome

AF:

0.146

Gnomad EAS exome

AF:

0.251

Gnomad SAS exome

AF:

0.0860

Gnomad FIN exome

AF:

0.131

Gnomad NFE exome

AF:

0.160

Gnomad OTH exome

AF:

0.152

GnomAD4 exome

AF:

0.151

AC:

220619

AN:

1461376

Hom.:

17207

Cov.:

AF XY:

0.149

AC XY:

108622

AN XY:

727030

show subpopulations

Gnomad4 AFR exome

AF:

0.0887

Gnomad4 AMR exome

AF:

0.102

Gnomad4 ASJ exome

AF:

0.145

Gnomad4 EAS exome

AF:

0.220

Gnomad4 SAS exome

AF:

0.0879

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.158

Gnomad4 OTH exome

AF:

0.150

GnomAD4 genome

AF:

0.138

AC:

20952

AN:

151870

Hom.:

1564

Cov.:

AF XY:

0.138

AC XY:

10238

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.0933

Gnomad4 AMR

AF:

0.132

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.232

Gnomad4 SAS

AF:

0.0907

Gnomad4 FIN

AF:

0.137

Gnomad4 NFE

AF:

0.158

Gnomad4 OTH

AF:

0.157

Alfa

AF:

0.152

Hom.:

2998

Bravo

AF:

0.138

Asia WGS

AF:

0.130

AC:

452

AN:

3478

EpiCase

AF:

0.162

EpiControl

AF:

0.167

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 21, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 09, 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

- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:2

Jun 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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

-0.92

CADD

Benign

0.16

DANN

Benign

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

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

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