NM_001845.6:c.2130G>A

Variant names:

• chr13-110181355-C-T
• rs16975492
• NM_001845.6:c.2130G>A

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.2130G>A​(p.Pro710Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.356 in 1,612,120 control chromosomes in the GnomAD database, including 103,505 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8380 hom., cov: 31)
  • Exomes 𝑓: 0.36 (95125 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.01
• Publications: 23 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=-0.87).
• BP6: Variant 13-110181355-C-T is Benign according to our data. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110181355-C-T is described in CliVar as Benign. Clinvar id is 258249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.2130G>A	p.Pro710Pro	synonymous_variant	Exon 29 of 52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.2130G>A	p.Pro710Pro	synonymous_variant	Exon 29 of 52	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49626 AN: 151264 Hom.: 8368 Cov.: 31

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.343

Gnomad EAS AF: 0.293

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.343

GnomAD2 exomes AF: 0.351 AC: 87621 AN: 249938 AF XY: 0.352

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.390

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.293

Gnomad FIN exome AF: 0.351

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.344

GnomAD4 exome AF: 0.359 AC: 523824 AN: 1460740 Hom.: 95125 Cov.: 41 AF XY: 0.359 AC XY: 261125 AN XY: 726648

African (AFR) AF: 0.232 AC: 7755 AN: 33468

American (AMR) AF: 0.388 AC: 17309 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 8351 AN: 26118

East Asian (EAS) AF: 0.257 AC: 10183 AN: 39670

South Asian (SAS) AF: 0.373 AC: 32146 AN: 86174

European-Finnish (FIN) AF: 0.356 AC: 18972 AN: 53362

Middle Eastern (MID) AF: 0.266 AC: 1527 AN: 5750

European-Non Finnish (NFE) AF: 0.366 AC: 406517 AN: 1111226

Other (OTH) AF: 0.349 AC: 21064 AN: 60342

GnomAD4 genome AF: 0.328 AC: 49665 AN: 151380 Hom.: 8380 Cov.: 31 AF XY: 0.329 AC XY: 24300 AN XY: 73876

African (AFR) AF: 0.239 AC: 9862 AN: 41248

American (AMR) AF: 0.356 AC: 5431 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 1190 AN: 3468

East Asian (EAS) AF: 0.293 AC: 1502 AN: 5118

South Asian (SAS) AF: 0.371 AC: 1770 AN: 4776

European-Finnish (FIN) AF: 0.353 AC: 3684 AN: 10432

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24902 AN: 67804

Other (OTH) AF: 0.349 AC: 730 AN: 2094

Alfa AF: 0.345 Hom.: 12461

Bravo AF: 0.324

Asia WGS AF: 0.354 AC: 1230 AN: 3478

EpiCase AF: 0.353

EpiControl AF: 0.353

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 02, 2021

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 19, 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. -

-

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

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

- -

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. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.74
DANN	Benign	0.41
PhyloP100		-5.0
Mutation Taster		=96/4	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: rs16975492; hg19: chr13-110833702; COSMIC: COSV65427049;