chr13-110205548-A-G

Position:

• chr13-110205548-A-G

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.859-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.633 in 1,610,452 control chromosomes in the GnomAD database, including 326,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (26221 hom., cov: 32)
  • Exomes 𝑓: 0.64 (300359 hom.)
• Consequence: COL4A1 NM_001845.6 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0004416
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.07

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=-0.83).
• BP6: Variant 13-110205548-A-G is Benign according to our data. Variant chr13-110205548-A-G is described in ClinVar as [Benign]. Clinvar id is 258265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110205548-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.741 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.859-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375820.10
COL4A1	NM_001303110.2	c.859-10T>C		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.859-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001845.6	P1

Frequencies

GnomAD3 genomes AF: 0.580 AC: 87566 AN: 151050 Hom.: 26225 Cov.: 32

Gnomad AFR AF: 0.429

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.546

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.610

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.622

GnomAD3 exomes AF: 0.622 AC: 156273 AN: 251358 Hom.: 49856 AF XY: 0.633 AC XY: 86011 AN XY: 135878

Gnomad AFR exome AF: 0.416

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.703

Gnomad EAS exome AF: 0.763

Gnomad SAS exome AF: 0.689

Gnomad FIN exome AF: 0.606

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.642

GnomAD4 exome AF: 0.639 AC: 931871 AN: 1459286 Hom.: 300359 Cov.: 41 AF XY: 0.641 AC XY: 465778 AN XY: 726112

Gnomad4 AFR exome AF: 0.407

Gnomad4 AMR exome AF: 0.500

Gnomad4 ASJ exome AF: 0.705

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.607

Gnomad4 NFE exome AF: 0.642

Gnomad4 OTH exome AF: 0.640

GnomAD4 genome AF: 0.579 AC: 87578 AN: 151166 Hom.: 26221 Cov.: 32 AF XY: 0.582 AC XY: 42947 AN XY: 73840

Gnomad4 AFR AF: 0.429

Gnomad4 AMR AF: 0.545

Gnomad4 ASJ AF: 0.700

Gnomad4 EAS AF: 0.761

Gnomad4 SAS AF: 0.701

Gnomad4 FIN AF: 0.610

Gnomad4 NFE AF: 0.638

Gnomad4 OTH AF: 0.619

Alfa AF: 0.598 Hom.: 8722

Bravo AF: 0.566

Asia WGS AF: 0.686 AC: 2386 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2017	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	- -

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

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	- -

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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Porencephalic cyst Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.010
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: rs677877; hg19: chr13-110857895; COSMIC: COSV104687934; COSMIC: COSV104687934;