13-110213718-C-T

Variant names:

• chr13-110213718-C-T
• rs3737328
• NM_001845.6:c.279+64G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001845.6(COL4A1):​c.279+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 1,530,950 control chromosomes in the GnomAD database, including 41,887 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (3878 hom., cov: 31)
  • Exomes 𝑓: 0.23 (38009 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.646
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 13-110213718-C-T is Benign according to our data. Variant chr13-110213718-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.296 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001845.6. 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
	COL4A1	NM_001845.6	MANE Select	c.279+64G>A		intron	N/A	NP_001836.3
	COL4A1	NM_001303110.2		c.279+64G>A		intron	N/A	NP_001290039.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.279+64G>A		intron	N/A	ENSP00000364979.4
	COL4A1	ENST00000543140.6	TSL:1	c.279+64G>A		intron	N/A	ENSP00000443348.1
	COL4A1	ENST00000650424.2		c.279+64G>A		intron	N/A	ENSP00000497477.2

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34321 AN: 151886 Hom.: 3875 Cov.: 31

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.201

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.308

Gnomad SAS AF: 0.184

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.244

GnomAD4 exome AF: 0.232 AC: 320548 AN: 1378946 Hom.: 38009 AF XY: 0.231 AC XY: 159471 AN XY: 690680

African (AFR) AF: 0.210 AC: 6670 AN: 31832

American (AMR) AF: 0.161 AC: 7160 AN: 44430

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 4850 AN: 25604

East Asian (EAS) AF: 0.296 AC: 11614 AN: 39244

South Asian (SAS) AF: 0.181 AC: 15311 AN: 84542

European-Finnish (FIN) AF: 0.204 AC: 10860 AN: 53280

Middle Eastern (MID) AF: 0.193 AC: 981 AN: 5082

European-Non Finnish (NFE) AF: 0.241 AC: 249745 AN: 1037352

Other (OTH) AF: 0.232 AC: 13357 AN: 57580

GnomAD4 genome AF: 0.226 AC: 34345 AN: 152004 Hom.: 3878 Cov.: 31 AF XY: 0.225 AC XY: 16691 AN XY: 74310

African (AFR) AF: 0.208 AC: 8637 AN: 41448

American (AMR) AF: 0.200 AC: 3058 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3472

East Asian (EAS) AF: 0.308 AC: 1593 AN: 5170

South Asian (SAS) AF: 0.184 AC: 887 AN: 4814

European-Finnish (FIN) AF: 0.199 AC: 2103 AN: 10572

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16387 AN: 67946

Other (OTH) AF: 0.241 AC: 508 AN: 2108

Alfa AF: 0.224 Hom.: 2215

Bravo AF: 0.226

Asia WGS AF: 0.223 AC: 775 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.7
DANN	Benign	0.68
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3737328; hg19: chr13-110866065; COSMIC: COSV65422564;