rs117738194

Positions:

• chr13-110170596-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001845.6(COL4A1):​c.3693G>A​(p.Thr1231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,610,634 control chromosomes in the GnomAD database, including 445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (49 hom., cov: 33)
  • Exomes 𝑓: 0.0067 (396 hom.)
• Consequence: COL4A1 NM_001845.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.223

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 13-110170596-C-T is Benign according to our data. Variant chr13-110170596-C-T is described in ClinVar as [Benign]. Clinvar id is 258252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110170596-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.223 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0688 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3693G>A	p.Thr1231=	synonymous_variant	42/52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3693G>A	p.Thr1231=	synonymous_variant	42/52	1	NM_001845.6	ENSP00000364979	P1

Frequencies

GnomAD3 genomes AF: 0.00862 AC: 1312 AN: 152246 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0459

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.0745

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00132

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.0221 AC: 5323 AN: 240386 Hom.: 287 AF XY: 0.0175 AC XY: 2290 AN XY: 130622

Gnomad AFR exome AF: 0.00213

Gnomad AMR exome AF: 0.104

Gnomad ASJ exome AF: 0.00521

Gnomad EAS exome AF: 0.0822

Gnomad SAS exome AF: 0.000873

Gnomad FIN exome AF: 0.000142

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.0163

GnomAD4 exome AF: 0.00668 AC: 9743 AN: 1458270 Hom.: 396 Cov.: 32 AF XY: 0.00603 AC XY: 4374 AN XY: 725164

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.0978

Gnomad4 ASJ exome AF: 0.00527

Gnomad4 EAS exome AF: 0.0722

Gnomad4 SAS exome AF: 0.00130

Gnomad4 FIN exome AF: 0.000188

Gnomad4 NFE exome AF: 0.00157

Gnomad4 OTH exome AF: 0.00834

GnomAD4 genome AF: 0.00868 AC: 1323 AN: 152364 Hom.: 49 Cov.: 33 AF XY: 0.00925 AC XY: 689 AN XY: 74508

Gnomad4 AFR AF: 0.00204

Gnomad4 AMR AF: 0.0464

Gnomad4 ASJ AF: 0.00663

Gnomad4 EAS AF: 0.0749

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00374 Hom.: 4

Bravo AF: 0.0145

Asia WGS AF: 0.0240 AC: 83 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Brain small vessel disease 1 with or without ocular anomalies Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
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. -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.1
DANN	Benign	0.43

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: rs117738194; hg19: chr13-110822943;