13-110207396-C-T

Position:

• chr13-110207396-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.780+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,607,206 control chromosomes in the GnomAD database, including 325,232 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26153 hom., cov: 32)
  • Exomes 𝑓: 0.64 (299079 hom.)
• Consequence: COL4A1 NM_001845.6 splice_region, intron
• Scores: Splicing: ADA: 0.000007063
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -3.17

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-110207396-C-T is Benign according to our data. Variant chr13-110207396-C-T is described in ClinVar as [Benign]. Clinvar id is 258262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110207396-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.780+7G>A		splice_region_variant, intron_variant		ENST00000375820.10
COL4A1	NM_001303110.2	c.780+7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.780+7G>A		splice_region_variant, intron_variant		1	NM_001845.6	P1

Frequencies

GnomAD3 genomes AF: 0.577 AC: 87531 AN: 151794 Hom.: 26156 Cov.: 32

Gnomad AFR AF: 0.422

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.699

Gnomad EAS AF: 0.759

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.620 AC: 155997 AN: 251422 Hom.: 49690 AF XY: 0.632 AC XY: 85853 AN XY: 135890

Gnomad AFR exome AF: 0.414

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.757

Gnomad SAS exome AF: 0.688

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.642

Gnomad OTH exome AF: 0.641

GnomAD4 exome AF: 0.638 AC: 928192 AN: 1455294 Hom.: 299079 Cov.: 33 AF XY: 0.641 AC XY: 464145 AN XY: 724398

Gnomad4 AFR exome AF: 0.402

Gnomad4 AMR exome AF: 0.498

Gnomad4 ASJ exome AF: 0.704

Gnomad4 EAS exome AF: 0.772

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.639

GnomAD4 genome AF: 0.576 AC: 87543 AN: 151912 Hom.: 26153 Cov.: 32 AF XY: 0.578 AC XY: 42919 AN XY: 74238

Gnomad4 AFR AF: 0.422

Gnomad4 AMR AF: 0.544

Gnomad4 ASJ AF: 0.699

Gnomad4 EAS AF: 0.758

Gnomad4 SAS AF: 0.700

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.638

Gnomad4 OTH AF: 0.619

Alfa AF: 0.628 Hom.: 38928

Bravo AF: 0.565

Asia WGS AF: 0.684 AC: 2380 AN: 3478

EpiCase AF: 0.656

EpiControl AF: 0.660

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
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	-0.91
CADD	Benign	0.059
DANN	Benign	0.38

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000071
dbscSNV1_RF	Benign	0.0
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: rs598893; hg19: chr13-110859743; COSMIC: COSV65426470;