rs10492497

chr13-110179519-T-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.2194-98A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0752 in 1,537,726 control chromosomes in the GnomAD database, including 4,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.076 (437 hom., cov: 33)
  • Exomes 𝑓: 0.075 (4251 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.40

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 13-110179519-T-C is Benign according to our data. Variant chr13-110179519-T-C is described in ClinVar as [Benign]. Clinvar id is 1293322.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-110179519-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.2194-98A>G		intron_variant		ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.2194-98A>G		intron_variant		1	NM_001845.6	P1
COL4A1	ENST00000649738.1	n.2324-98A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0759 AC: 11558 AN: 152180 Hom.: 437 Cov.: 33

Gnomad AFR AF: 0.0761

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0871

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.0646

Gnomad FIN AF: 0.0924

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0716

Gnomad OTH AF: 0.0784

GnomAD4 exome AF: 0.0752 AC: 104134 AN: 1385428 Hom.: 4251 AF XY: 0.0744 AC XY: 51587 AN XY: 693370

Gnomad4 AFR exome AF: 0.0758

Gnomad4 AMR exome AF: 0.119

Gnomad4 ASJ exome AF: 0.0169

Gnomad4 EAS exome AF: 0.138

Gnomad4 SAS exome AF: 0.0673

Gnomad4 FIN exome AF: 0.0878

Gnomad4 NFE exome AF: 0.0731

Gnomad4 OTH exome AF: 0.0679

GnomAD4 genome AF: 0.0760 AC: 11570 AN: 152298 Hom.: 437 Cov.: 33 AF XY: 0.0777 AC XY: 5783 AN XY: 74466

Gnomad4 AFR AF: 0.0762

Gnomad4 AMR AF: 0.0870

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.0644

Gnomad4 FIN AF: 0.0924

Gnomad4 NFE AF: 0.0717

Gnomad4 OTH AF: 0.0781

Alfa AF: 0.0700 Hom.: 551

Bravo AF: 0.0779

Asia WGS AF: 0.0970 AC: 336 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.21
Dann	Benign	0.29

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: rs10492497; hg19: chr13-110831866; COSMIC: COSV65430829;