rs1133219

Variant names:

• chr13-110161362-G-A
• rs1133219
• NM_001845.6:c.4470C>T

Your query was ambiguous. Multiple possible variants found:

• chr13-110161362-G-A
• chr13-110161362-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):​c.4470C>T​(p.Ala1490Ala) 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -2.54
• Publications: 22 publications found

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 Gene-Disease associations (from GenCC):

• brain small vessel disease 1 with or without ocular anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontine autosomal dominant microangiopathy with leukoencephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal arterial tortuosity

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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.
• 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 rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.4470C>T	p.Ala1490Ala	synonymous_variant	Exon 49 of 52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.4470C>T	p.Ala1490Ala	synonymous_variant	Exon 49 of 52	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53295 AN: 152048 Hom.: 9519 Cov.: 34

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

GnomAD2 exomes AF: 0.334 AC: 81567 AN: 244350 AF XY: 0.341

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 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.: 44 AF XY: 0.353 AC XY: 255815 AN XY: 724908

African (AFR) AF: 0.366 AC: 12227 AN: 33426

American (AMR) AF: 0.215 AC: 9483 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 9027 AN: 26074

East Asian (EAS) AF: 0.201 AC: 7971 AN: 39610

South Asian (SAS) AF: 0.381 AC: 32753 AN: 85902

European-Finnish (FIN) AF: 0.425 AC: 22550 AN: 53030

Middle Eastern (MID) AF: 0.361 AC: 2082 AN: 5762

European-Non Finnish (NFE) AF: 0.355 AC: 394462 AN: 1109792

Other (OTH) AF: 0.347 AC: 20891 AN: 60246

GnomAD4 genome AF: 0.350 AC: 53328 AN: 152166 Hom.: 9528 Cov.: 34 AF XY: 0.352 AC XY: 26191 AN XY: 74398

African (AFR) AF: 0.367 AC: 15240 AN: 41508

American (AMR) AF: 0.255 AC: 3897 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 1187 AN: 3466

East Asian (EAS) AF: 0.196 AC: 1014 AN: 5178

South Asian (SAS) AF: 0.360 AC: 1737 AN: 4826

European-Finnish (FIN) AF: 0.439 AC: 4637 AN: 10574

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.360 AC: 24476 AN: 68002

Other (OTH) AF: 0.345 AC: 729 AN: 2110

Alfa AF: 0.350 Hom.: 31306

Bravo AF: 0.330

Asia WGS AF: 0.297 AC: 1036 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

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

- -

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. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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

- -

Brain small vessel disease 1 with or without ocular anomalies Benign:2

Jan 13, 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 13, 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	-0.68
CADD	Benign	2.4
DANN	Benign	0.37
PhyloP100		-2.5
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1133219; hg19: chr13-110813709; COSMIC: COSV65431721; COSMIC: COSV65431721;