rs35466678

Variant names:

• chr13-110307440-A-G
• rs35466678
• NM_001846.4:c.-133A>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001846.4(COL4A2):​c.-133A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 200,010 control chromosomes in the GnomAD database, including 2,717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2028 hom., cov: 32)
  • Exomes 𝑓: 0.16 (689 hom.)
• Consequence: COL4A2 NM_001846.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.245

Genes affected

COL4A2 (HGNC:2203): (collagen type IV alpha 2 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 13-110307440-A-G is Benign according to our data. Variant chr13-110307440-A-G is described in ClinVar as [Benign]. Clinvar id is 311093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.-133A>G		5_prime_UTR_variant	Exon 1 of 48	ENST00000360467.7	NP_001837.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467	c.-133A>G		5_prime_UTR_variant	Exon 1 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23843 AN: 151678 Hom.: 2026 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.208

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.276

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.192

GnomAD4 exome AF: 0.156 AC: 7503 AN: 48222 Hom.: 689 Cov.: 0 AF XY: 0.157 AC XY: 3829 AN XY: 24340

Gnomad4 AFR exome AF: 0.116

Gnomad4 AMR exome AF: 0.233

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.282

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.0788

Gnomad4 NFE exome AF: 0.144

Gnomad4 OTH exome AF: 0.163

GnomAD4 genome AF: 0.157 AC: 23862 AN: 151788 Hom.: 2028 Cov.: 32 AF XY: 0.159 AC XY: 11783 AN XY: 74146

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.217

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.279

Gnomad4 SAS AF: 0.208

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.152

Gnomad4 OTH AF: 0.191

Alfa AF: 0.147 Hom.: 208

Bravo AF: 0.165

Asia WGS AF: 0.199 AC: 688 AN: 3470

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 21, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Brain small vessel disease 1 with or without ocular anomalies Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Porencephaly 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Porencephalic cyst Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.7
DANN	Benign	0.60

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: rs35466678; hg19: chr13-110959787; COSMIC: COSV64634774; COSMIC: COSV64634774;