rs2275842

Positions:

• chr13-110161176-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.4640+16G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.161 in 1,610,684 control chromosomes in the GnomAD database, including 21,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1880 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19953 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0310

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 13-110161176-C-T is Benign according to our data. Variant chr13-110161176-C-T is described in ClinVar as [Benign]. Clinvar id is 258256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110161176-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.4640+16G>A		intron_variant		ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.4640+16G>A		intron_variant		1	NM_001845.6	ENSP00000364979	P1
COL4A1	ENST00000650424.1	c.796+16G>A		intron_variant				ENSP00000497477
COL4A1	ENST00000467182.1	n.435G>A		non_coding_transcript_exon_variant	3/3	3
COL4A1	ENST00000649720.1	n.808+16G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23223 AN: 152064 Hom.: 1881 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.323

Gnomad SAS AF: 0.192

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.184

GnomAD3 exomes AF: 0.166 AC: 41781 AN: 250984 Hom.: 3683 AF XY: 0.166 AC XY: 22527 AN XY: 135660

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.181

Gnomad ASJ exome AF: 0.168

Gnomad EAS exome AF: 0.303

Gnomad SAS exome AF: 0.175

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.180

GnomAD4 exome AF: 0.161 AC: 235388 AN: 1458502 Hom.: 19953 Cov.: 30 AF XY: 0.161 AC XY: 117161 AN XY: 725738

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.312

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.157

Gnomad4 OTH exome AF: 0.172

GnomAD4 genome AF: 0.153 AC: 23235 AN: 152182 Hom.: 1880 Cov.: 33 AF XY: 0.154 AC XY: 11438 AN XY: 74402

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.155

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.191

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.156

Gnomad4 OTH AF: 0.183

Alfa AF: 0.154 Hom.: 325

Bravo AF: 0.158

Asia WGS AF: 0.261 AC: 906 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.37

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: rs2275842; hg19: chr13-110813523; COSMIC: COSV65423059; COSMIC: COSV65423059;