rs2166207

chr13-110209921-A-Cchr13-110209921-A-T

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+59T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 1,550,788 control chromosomes in the GnomAD database, including 104,323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.40 (12663 hom., cov: 32)
  • Exomes 𝑓: 0.36 (91660 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.934

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=-0.85).
• BP6: Variant 13-110209921-A-C is Benign according to our data. Variant chr13-110209921-A-C is described in ClinVar as [Benign]. Clinvar id is 1272047.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-110209921-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.615+59T>G		intron_variant		ENST00000375820.10
COL4A1	NM_001303110.2	c.615+59T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.615+59T>G		intron_variant		1	NM_001845.6	P1

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60740 AN: 151962 Hom.: 12633 Cov.: 32

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.301

Gnomad EAS AF: 0.242

Gnomad SAS AF: 0.302

Gnomad FIN AF: 0.390

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.374 AC: 93290 AN: 249314 Hom.: 18442 AF XY: 0.365 AC XY: 49355 AN XY: 135318

Gnomad AFR exome AF: 0.506

Gnomad AMR exome AF: 0.502

Gnomad ASJ exome AF: 0.298

Gnomad EAS exome AF: 0.242

Gnomad SAS exome AF: 0.312

Gnomad FIN exome AF: 0.395

Gnomad NFE exome AF: 0.359

Gnomad OTH exome AF: 0.355

GnomAD4 exome AF: 0.357 AC: 499675 AN: 1398708 Hom.: 91660 Cov.: 23 AF XY: 0.355 AC XY: 248490 AN XY: 699872

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.499

Gnomad4 ASJ exome AF: 0.295

Gnomad4 EAS exome AF: 0.228

Gnomad4 SAS exome AF: 0.315

Gnomad4 FIN exome AF: 0.394

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.400 AC: 60829 AN: 152080 Hom.: 12663 Cov.: 32 AF XY: 0.399 AC XY: 29669 AN XY: 74342

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.449

Gnomad4 ASJ AF: 0.301

Gnomad4 EAS AF: 0.243

Gnomad4 SAS AF: 0.301

Gnomad4 FIN AF: 0.390

Gnomad4 NFE AF: 0.363

Gnomad4 OTH AF: 0.364

Alfa AF: 0.369 Hom.: 1937

Bravo AF: 0.409

Asia WGS AF: 0.313 AC: 1087 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 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	4.4
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2166207; hg19: chr13-110862268; COSMIC: COSV65421521;