rs75270666

Positions:

• chr13-110242853-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001845.6(COL4A1):​c.85-119C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00968 in 1,100,190 control chromosomes in the GnomAD database, including 480 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.012 (78 hom., cov: 33)
  • Exomes 𝑓: 0.0092 (402 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.525

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.85-119C>T		intron_variant		ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.85-119C>T		intron_variant			NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.85-119C>T		intron_variant		1	NM_001845.6	ENSP00000364979	P1
COL4A1	ENST00000543140.6	c.85-119C>T		intron_variant		1		ENSP00000443348
COL4A1	ENST00000615732.2	c.-108-119C>T		intron_variant		5		ENSP00000478222
COL4A1	ENST00000649738.1	n.215-119C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1898 AN: 152166 Hom.: 78 Cov.: 33

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0799

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.0426

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00956

GnomAD4 exome AF: 0.00923 AC: 8751 AN: 947906 Hom.: 402 AF XY: 0.00798 AC XY: 3937 AN XY: 493516

Gnomad4 AFR exome AF: 0.00193

Gnomad4 AMR exome AF: 0.121

Gnomad4 ASJ exome AF: 0.00495

Gnomad4 EAS exome AF: 0.0443

Gnomad4 SAS exome AF: 0.00134

Gnomad4 FIN exome AF: 0.0227

Gnomad4 NFE exome AF: 0.000415

Gnomad4 OTH exome AF: 0.00846

GnomAD4 genome AF: 0.0125 AC: 1902 AN: 152284 Hom.: 78 Cov.: 33 AF XY: 0.0153 AC XY: 1140 AN XY: 74450

Gnomad4 AFR AF: 0.00188

Gnomad4 AMR AF: 0.0801

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.0427

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0283

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00601 Hom.: 5

Bravo AF: 0.0170

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.1
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: rs75270666; hg19: chr13-110895200; COSMIC: COSV65433493;