rs12428227

chr13-110249945-A-G

Variant summary

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

The NM_001845.6(COL4A1):c.85-7211T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,138 control chromosomes in the GnomAD database, including 1,613 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 0.14 (1613 hom., cov: 32)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141

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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A1	NM_001845.6	c.85-7211T>C		intron_variant		ENST00000375820.10
COL4A1	NM_001303110.2	c.85-7211T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A1	ENST00000375820.10	c.85-7211T>C		intron_variant		1	NM_001845.6	P1
COL4A1	ENST00000543140.6	c.85-7211T>C		intron_variant		1
COL4A1	ENST00000615732.2	c.-108-7211T>C		intron_variant		5
COL4A1	ENST00000649738.1	n.215-7211T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21603 AN: 152018 Hom.: 1618 Cov.: 32

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.279

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0214

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.127

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.142 AC: 21612 AN: 152138 Hom.: 1613 Cov.: 32 AF XY: 0.140 AC XY: 10415 AN XY: 74388

Gnomad4 AFR AF: 0.119

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0216

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.169

Gnomad4 OTH AF: 0.125

Alfa AF: 0.163 Hom.: 629

Bravo AF: 0.137

Asia WGS AF: 0.0860 AC: 301 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.0
Dann	Benign	0.76

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: rs12428227; hg19: chr13-110902292;