rs35638294

Variant names:

• chr13-110209273-T-TAAAG
• rs35638294
• NM_001845.6:c.651+118_651+119insCTTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.651+118_651+119insCTTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.246 in 794,442 control chromosomes in the GnomAD database, including 26,206 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.25 (4891 hom., cov: 24)
  • Exomes 𝑓: 0.25 (21315 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.208
• Publications: 1 publications found

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]

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 -10 ACMG points.

• BP6: Variant 13-110209273-T-TAAAG is Benign according to our data. Variant chr13-110209273-T-TAAAG is described in ClinVar as Benign. ClinVar VariationId is 1181737.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.308 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.651+118_651+119insCTTT		intron_variant	Intron 11 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2	c.651+118_651+119insCTTT		intron_variant	Intron 11 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.651+118_651+119insCTTT		intron_variant	Intron 11 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37330 AN: 151918 Hom.: 4884 Cov.: 24

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0458

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.242

Gnomad NFE AF: 0.266

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.247 AC: 158376 AN: 642406 Hom.: 21315 AF XY: 0.246 AC XY: 85013 AN XY: 345438

African (AFR) AF: 0.203 AC: 3320 AN: 16366

American (AMR) AF: 0.319 AC: 9793 AN: 30702

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 4298 AN: 18264

East Asian (EAS) AF: 0.0304 AC: 1091 AN: 35906

South Asian (SAS) AF: 0.225 AC: 13298 AN: 59102

European-Finnish (FIN) AF: 0.310 AC: 15579 AN: 50272

Middle Eastern (MID) AF: 0.238 AC: 731 AN: 3070

European-Non Finnish (NFE) AF: 0.259 AC: 102421 AN: 396074

Other (OTH) AF: 0.240 AC: 7845 AN: 32650

GnomAD4 genome AF: 0.246 AC: 37370 AN: 152036 Hom.: 4891 Cov.: 24 AF XY: 0.248 AC XY: 18448 AN XY: 74314

African (AFR) AF: 0.203 AC: 8407 AN: 41474

American (AMR) AF: 0.316 AC: 4820 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 847 AN: 3472

East Asian (EAS) AF: 0.0455 AC: 236 AN: 5184

South Asian (SAS) AF: 0.212 AC: 1024 AN: 4824

European-Finnish (FIN) AF: 0.320 AC: 3376 AN: 10550

Middle Eastern (MID) AF: 0.247 AC: 72 AN: 292

European-Non Finnish (NFE) AF: 0.266 AC: 18070 AN: 67948

Other (OTH) AF: 0.217 AC: 459 AN: 2112

Alfa AF: 0.247 Hom.: 278

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.21
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35638294; hg19: chr13-110861620; COSMIC: COSV107488033;