rs1133219

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001845.6(COL4A1):c.4470C>T(p.Ala1490=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,610,064 control chromosomes in the GnomAD database, including 100,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9528 hom., cov: 34)

Exomes 𝑓: 0.35 ( 90952 hom. )

Consequence

COL4A1
NM_001845.6 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -2.54

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 13-110161362-G-A is Benign according to our data. Variant chr13-110161362-G-A is described in ClinVar as [Benign]. Clinvar id is 258255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110161362-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-2.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6 linkuse as main transcript	c.4470C>T	p.Ala1490=	synonymous_variant	49/52	ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10 linkuse as main transcript	c.4470C>T	p.Ala1490=	synonymous_variant	49/52	1	NM_001845.6	P1	P02462-1
COL4A1	ENST00000650424.1 linkuse as main transcript	c.627C>T	p.Ala209=	synonymous_variant	7/10
COL4A1	ENST00000467182.1 linkuse as main transcript	n.249C>T		non_coding_transcript_exon_variant	3/3	3
COL4A1	ENST00000649720.1 linkuse as main transcript	n.638C>T		non_coding_transcript_exon_variant	4/7

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53295

AN:

152048

Hom.:

9519

Cov.:

show subpopulations

Gnomad AFR

AF:

0.368

Gnomad AMI

AF:

0.352

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.439

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.360

Gnomad OTH

AF:

0.341

GnomAD3 exomes

AF:

0.334

AC:

81567

AN:

244350

Hom.:

13987

AF XY:

0.341

AC XY:

44963

AN XY:

131966

show subpopulations

Gnomad AFR exome

AF:

0.366

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.205

Gnomad SAS exome

AF:

0.378

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.330

GnomAD4 exome

AF:

0.351

AC:

511446

AN:

1457898

Hom.:

90952

Cov.:

AF XY:

0.353

AC XY:

255815

AN XY:

724908

show subpopulations

Gnomad4 AFR exome

AF:

0.366

Gnomad4 AMR exome

AF:

0.215

Gnomad4 ASJ exome

AF:

0.346

Gnomad4 EAS exome

AF:

0.201

Gnomad4 SAS exome

AF:

0.381

Gnomad4 FIN exome

AF:

0.425

Gnomad4 NFE exome

AF:

0.355

Gnomad4 OTH exome

AF:

0.347

GnomAD4 genome

AF:

0.350

AC:

53328

AN:

152166

Hom.:

9528

Cov.:

AF XY:

0.352

AC XY:

26191

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.367

Gnomad4 AMR

AF:

0.255

Gnomad4 ASJ

AF:

0.342

Gnomad4 EAS

AF:

0.196

Gnomad4 SAS

AF:

0.360

Gnomad4 FIN

AF:

0.439

Gnomad4 NFE

AF:

0.360

Gnomad4 OTH

AF:

0.345

Alfa

AF:

0.351

Hom.:

15657

Bravo

AF:

0.330

Asia WGS

AF:

0.297

AC:

1036

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	-	- -
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. -

Brain small vessel disease 1 with or without ocular anomalies

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 13, 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. -

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 13, 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. -

Porencephalic cyst

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

Cadd

Benign

2.4

Dann

Benign

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

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