rs391859

Variant names:

• chr13-110507957-G-A
• rs391859
• NM_001846.4:c.4617G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001846.4(COL4A2):​c.4617G>A​(p.Ala1539Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0882 in 1,613,750 control chromosomes in the GnomAD database, including 7,318 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (795 hom., cov: 32)
  • Exomes 𝑓: 0.088 (6523 hom.)
• Consequence: COL4A2 NM_001846.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -4.66
• Publications: 18 publications found

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]

COL4A2-AS1 (HGNC:40156): (COL4A2 antisense RNA 1)

ENSG00000289010 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 13-110507957-G-A is Benign according to our data. Variant chr13-110507957-G-A is described in ClinVar as Benign. ClinVar VariationId is 311183.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A2	NM_001846.4	c.4617G>A	p.Ala1539Ala	synonymous_variant	Exon 47 of 48	ENST00000360467.7	NP_001837.2
COL4A2-AS1	NR_046583.1	n.81+142C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A2	ENST00000360467.7	c.4617G>A	p.Ala1539Ala	synonymous_variant	Exon 47 of 48	5	NM_001846.4	ENSP00000353654.5

Frequencies

GnomAD3 genomes AF: 0.0940 AC: 14296 AN: 152048 Hom.: 791 Cov.: 32

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.153

Gnomad SAS AF: 0.0625

Gnomad FIN AF: 0.0462

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0871

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.106 AC: 26210 AN: 248338 AF XY: 0.101

Gnomad AFR exome AF: 0.0797

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.0475

Gnomad NFE exome AF: 0.0872

Gnomad OTH exome AF: 0.108

GnomAD4 exome AF: 0.0876 AC: 128031 AN: 1461584 Hom.: 6523 Cov.: 31 AF XY: 0.0873 AC XY: 63503 AN XY: 727056

African (AFR) AF: 0.0787 AC: 2636 AN: 33480

American (AMR) AF: 0.204 AC: 9121 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4381 AN: 26136

East Asian (EAS) AF: 0.171 AC: 6803 AN: 39694

South Asian (SAS) AF: 0.0691 AC: 5961 AN: 86256

European-Finnish (FIN) AF: 0.0473 AC: 2518 AN: 53280

Middle Eastern (MID) AF: 0.114 AC: 656 AN: 5760

European-Non Finnish (NFE) AF: 0.0810 AC: 90087 AN: 1111872

Other (OTH) AF: 0.0972 AC: 5868 AN: 60386

GnomAD4 genome AF: 0.0941 AC: 14319 AN: 152166 Hom.: 795 Cov.: 32 AF XY: 0.0930 AC XY: 6922 AN XY: 74422

African (AFR) AF: 0.0786 AC: 3262 AN: 41520

American (AMR) AF: 0.177 AC: 2704 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 570 AN: 3464

East Asian (EAS) AF: 0.153 AC: 788 AN: 5152

South Asian (SAS) AF: 0.0621 AC: 300 AN: 4828

European-Finnish (FIN) AF: 0.0462 AC: 490 AN: 10616

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0871 AC: 5921 AN: 67980

Other (OTH) AF: 0.111 AC: 234 AN: 2112

Alfa AF: 0.0949 Hom.: 2476

Bravo AF: 0.106

Asia WGS AF: 0.103 AC: 358 AN: 3478

EpiCase AF: 0.0959

EpiControl AF: 0.0968

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 02, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Porencephaly 2 Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.24
DANN	Benign	0.88
PhyloP100		-4.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs391859; hg19: chr13-111160304; COSMIC: COSV64627362;