rs72654112

Positions:

• chr13-110183113-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.1991-16G>A 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 0.127 in 1,611,874 control chromosomes in the GnomAD database, including 13,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (980 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12914 hom.)
• Consequence: COL4A1 NM_001845.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0220

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=-0.81).
• BP6: Variant 13-110183113-C-T is Benign according to our data. Variant chr13-110183113-C-T is described in ClinVar as [Benign]. Clinvar id is 258248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110183113-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.1991-16G>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.1991-16G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001845.6	P1
COL4A1	ENST00000649738.1	n.2121-16G>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15892 AN: 152124 Hom.: 979 Cov.: 33

Gnomad AFR AF: 0.0537

Gnomad AMI AF: 0.191

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.00888

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.109 AC: 26702 AN: 244694 Hom.: 1763 AF XY: 0.115 AC XY: 15206 AN XY: 132556

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.0731

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.00259

Gnomad SAS exome AF: 0.152

Gnomad FIN exome AF: 0.130

Gnomad NFE exome AF: 0.131

Gnomad OTH exome AF: 0.113

GnomAD4 exome AF: 0.130 AC: 189325 AN: 1459632 Hom.: 12914 Cov.: 33 AF XY: 0.131 AC XY: 95132 AN XY: 725902

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.0738

Gnomad4 ASJ exome AF: 0.115

Gnomad4 EAS exome AF: 0.0172

Gnomad4 SAS exome AF: 0.148

Gnomad4 FIN exome AF: 0.127

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.104 AC: 15890 AN: 152242 Hom.: 980 Cov.: 33 AF XY: 0.103 AC XY: 7671 AN XY: 74428

Gnomad4 AFR AF: 0.0536

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.124

Gnomad4 EAS AF: 0.00890

Gnomad4 SAS AF: 0.145

Gnomad4 FIN AF: 0.126

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.116

Alfa AF: 0.113 Hom.: 210

Bravo AF: 0.0988

Asia WGS AF: 0.0760 AC: 263 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 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	-	- -

not provided Benign:1

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	-0.81
CADD	Benign	9.3
DANN	Benign	0.67

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: rs72654112; hg19: chr13-110835460; COSMIC: COSV65421618;