13-110198495-A-G

Variant names:

• chr13-110198495-A-G
• rs995224
• NM_001845.6:c.1257T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):​c.1257T>C​(p.Pro419Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,613,652 control chromosomes in the GnomAD database, including 59,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5286 hom., cov: 31)
  • Exomes 𝑓: 0.27 (54094 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -2.90

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 13-110198495-A-G is Benign according to our data. Variant chr13-110198495-A-G is described in ClinVar as [Benign]. Clinvar id is 258246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110198495-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.311 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.1257T>C	p.Pro419Pro	synonymous_variant	Exon 21 of 52	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.1257T>C	p.Pro419Pro	synonymous_variant	Exon 21 of 25		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.1257T>C	p.Pro419Pro	synonymous_variant	Exon 21 of 52	1	NM_001845.6	ENSP00000364979.4
COL4A1	ENST00000543140.6	c.1257T>C	p.Pro419Pro	synonymous_variant	Exon 21 of 25	1		ENSP00000443348.1
COL4A1	ENST00000647797.1	c.1134T>C	p.Pro378Pro	synonymous_variant	Exon 20 of 20			ENSP00000497756.2
COL4A1	ENST00000649738.1	n.1387T>C		non_coding_transcript_exon_variant	Exon 21 of 31

Frequencies

GnomAD3 genomes AF: 0.256 AC: 38945 AN: 151882 Hom.: 5276 Cov.: 31

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.0735

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.0483

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.278

Gnomad OTH AF: 0.231

GnomAD3 exomes AF: 0.260 AC: 65165 AN: 250958 Hom.: 9285 AF XY: 0.256 AC XY: 34819 AN XY: 135774

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.332

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.0449

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.276

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.267 AC: 389888 AN: 1461652 Hom.: 54094 Cov.: 60 AF XY: 0.266 AC XY: 193177 AN XY: 727114

Gnomad4 AFR exome AF: 0.222

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.241

Gnomad4 EAS exome AF: 0.0367

Gnomad4 SAS exome AF: 0.230

Gnomad4 FIN exome AF: 0.327

Gnomad4 NFE exome AF: 0.275

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.257 AC: 38989 AN: 152000 Hom.: 5286 Cov.: 31 AF XY: 0.258 AC XY: 19204 AN XY: 74296

Gnomad4 AFR AF: 0.218

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.0481

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.331

Gnomad4 NFE AF: 0.278

Gnomad4 OTH AF: 0.228

Alfa AF: 0.241 Hom.: 1540

Bravo AF: 0.251

Asia WGS AF: 0.131 AC: 458 AN: 3478

EpiCase AF: 0.263

EpiControl AF: 0.259

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

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

Significance: Benign

Review Status: no assertion criteria provided

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

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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. -

-

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:3

Jun 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

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. -

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 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.015
DANN	Benign	0.44

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

Other links and lift over

dbSNP: rs995224; hg19: chr13-110850842; COSMIC: COSV65427982;