rs9521649

chr13-110209956-G-Achr13-110209956-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001845.6(COL4A1):c.615+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,611,612 control chromosomes in the GnomAD database, including 53,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.24 (4616 hom., cov: 32)
  • Exomes 𝑓: 0.25 (48840 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.252

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 13-110209956-G-A is Benign according to our data. Variant chr13-110209956-G-A is described in ClinVar as [Benign]. Clinvar id is 1227525.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-110209956-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.615+24C>T		intron_variant		ENST00000375820.10
COL4A1	NM_001303110.2	c.615+24C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.615+24C>T		intron_variant		1	NM_001845.6	P1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35826 AN: 151916 Hom.: 4613 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.310

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.239

Gnomad NFE AF: 0.265

Gnomad OTH AF: 0.211

GnomAD3 exomes AF: 0.247 AC: 61989 AN: 251132 Hom.: 8443 AF XY: 0.245 AC XY: 33324 AN XY: 135808

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.326

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0407

Gnomad SAS exome AF: 0.223

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.253 AC: 368965 AN: 1459578 Hom.: 48840 Cov.: 33 AF XY: 0.253 AC XY: 183404 AN XY: 726262

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.0322

Gnomad4 SAS exome AF: 0.229

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.237

GnomAD4 genome AF: 0.236 AC: 35850 AN: 152034 Hom.: 4616 Cov.: 32 AF XY: 0.239 AC XY: 17762 AN XY: 74304

Gnomad4 AFR AF: 0.168

Gnomad4 AMR AF: 0.310

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.0465

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.265

Gnomad4 OTH AF: 0.209

Alfa AF: 0.253 Hom.: 1531

Bravo AF: 0.228

Asia WGS AF: 0.125 AC: 435 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.18
Dann	Benign	0.47

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: rs9521649; hg19: chr13-110862303; COSMIC: COSV65423082;