rs2298240

Positions:

• chr13-110163326-C-G
• chr13-110163326-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.4249+137G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 764,244 control chromosomes in the GnomAD database, including 5,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.088 (793 hom., cov: 33)
  • Exomes 𝑓: 0.11 (4318 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.311

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=-0.84).
• BP6: Variant 13-110163326-C-G is Benign according to our data. Variant chr13-110163326-C-G is described in ClinVar as [Benign]. Clinvar id is 1231553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.4249+137G>C		intron_variant		ENST00000375820.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.4249+137G>C		intron_variant		1	NM_001845.6	P1

Frequencies

GnomAD3 genomes AF: 0.0883 AC: 13433 AN: 152144 Hom.: 794 Cov.: 33

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0907

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.0966

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.100

GnomAD4 exome AF: 0.113 AC: 69083 AN: 611982 Hom.: 4318 AF XY: 0.115 AC XY: 37389 AN XY: 326444

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0758

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.0326

Gnomad4 SAS exome AF: 0.119

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.0882 AC: 13426 AN: 152262 Hom.: 793 Cov.: 33 AF XY: 0.0867 AC XY: 6452 AN XY: 74450

Gnomad4 AFR AF: 0.0228

Gnomad4 AMR AF: 0.0906

Gnomad4 ASJ AF: 0.134

Gnomad4 EAS AF: 0.0141

Gnomad4 SAS AF: 0.120

Gnomad4 FIN AF: 0.0966

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.0993

Alfa AF: 0.0350 Hom.: 36

Bravo AF: 0.0841

Asia WGS AF: 0.0650 AC: 225 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	9.0
DANN	Benign	0.53

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: rs2298240; hg19: chr13-110815673;