rs35466678

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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]

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]

COL4A1 Gene-Disease associations (from GenCC):

• brain small vessel disease 1 with or without ocular anomalies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Orphanet, Genomics England PanelApp
• autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Ambry Genetics
• microangiopathy and leukoencephalopathy, pontine, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• familial porencephaly

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• pontine autosomal dominant microangiopathy with leukoencephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinal arterial tortuosity

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• muscular dystrophy-dystroglycanopathy, type A

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001846.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	NM_001846.4	MANE Select	c.-133A>G		5_prime_UTR	Exon 1 of 48	NP_001837.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A2	ENST00000360467.7	TSL:5 MANE Select	c.-133A>G		5_prime_UTR	Exon 1 of 48	ENSP00000353654.5
	COL4A2	ENST00000480771.5	TSL:4	n.174A>G		non_coding_transcript_exon	Exon 1 of 4
	COL4A2	ENST00000714397.1		n.-133A>G		non_coding_transcript_exon	Exon 1 of 49	ENSP00000519664.1

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

African (AFR) AF: 0.116 AC: 213 AN: 1832

American (AMR) AF: 0.233 AC: 299 AN: 1286

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 398 AN: 1938

East Asian (EAS) AF: 0.282 AC: 998 AN: 3542

South Asian (SAS) AF: 0.194 AC: 101 AN: 520

European-Finnish (FIN) AF: 0.0788 AC: 257 AN: 3262

Middle Eastern (MID) AF: 0.224 AC: 69 AN: 308

European-Non Finnish (NFE) AF: 0.144 AC: 4633 AN: 32242

Other (OTH) AF: 0.163 AC: 535 AN: 3292

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

African (AFR) AF: 0.131 AC: 5422 AN: 41456

American (AMR) AF: 0.217 AC: 3315 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 761 AN: 3472

East Asian (EAS) AF: 0.279 AC: 1406 AN: 5036

South Asian (SAS) AF: 0.208 AC: 1000 AN: 4804

European-Finnish (FIN) AF: 0.102 AC: 1076 AN: 10572

Middle Eastern (MID) AF: 0.276 AC: 80 AN: 290

European-Non Finnish (NFE) AF: 0.152 AC: 10319 AN: 67876

Other (OTH) AF: 0.191 AC: 402 AN: 2108

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	9.7
DANN	Benign	0.60
PhyloP100		-0.24
PromoterAI		-0.021	Neutral
Mutation Taster		=298/2	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: rs35466678; hg19: chr13-110959787; COSMIC: COSV64634774; COSMIC: COSV64634774;