rs1213026

Variant names:

• chr13-110167015-A-G
• rs1213026
• NM_001845.6:c.3949+143T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001845.6(COL4A1):​c.3949+143T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 768,236 control chromosomes in the GnomAD database, including 162,858 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.62 (29757 hom., cov: 33)
  • Exomes 𝑓: 0.65 (133101 hom.)
• Consequence: COL4A1 NM_001845.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0430
• Publications: 8 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 13-110167015-A-G is Benign according to our data. Variant chr13-110167015-A-G is described in ClinVar as [Benign]. Clinvar id is 1236593.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6	c.3949+143T>C		intron_variant	Intron 44 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10	c.3949+143T>C		intron_variant	Intron 44 of 51	1	NM_001845.6	ENSP00000364979.4

Frequencies

GnomAD3 genomes AF: 0.621 AC: 94346 AN: 151978 Hom.: 29752 Cov.: 33

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.683

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.657

Gnomad OTH AF: 0.616

GnomAD4 exome AF: 0.655 AC: 403497 AN: 616140 Hom.: 133101 AF XY: 0.655 AC XY: 218283 AN XY: 333148

African (AFR) AF: 0.507 AC: 8795 AN: 17334

American (AMR) AF: 0.718 AC: 29937 AN: 41680

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 12564 AN: 20300

East Asian (EAS) AF: 0.595 AC: 21176 AN: 35580

South Asian (SAS) AF: 0.662 AC: 45167 AN: 68182

European-Finnish (FIN) AF: 0.727 AC: 31122 AN: 42788

Middle Eastern (MID) AF: 0.609 AC: 1512 AN: 2484

European-Non Finnish (NFE) AF: 0.653 AC: 232147 AN: 355404

Other (OTH) AF: 0.651 AC: 21077 AN: 32388

GnomAD4 genome AF: 0.621 AC: 94391 AN: 152096 Hom.: 29757 Cov.: 33 AF XY: 0.626 AC XY: 46531 AN XY: 74358

African (AFR) AF: 0.512 AC: 21209 AN: 41438

American (AMR) AF: 0.674 AC: 10295 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 2128 AN: 3470

East Asian (EAS) AF: 0.614 AC: 3184 AN: 5184

South Asian (SAS) AF: 0.681 AC: 3284 AN: 4820

European-Finnish (FIN) AF: 0.725 AC: 7682 AN: 10590

Middle Eastern (MID) AF: 0.629 AC: 185 AN: 294

European-Non Finnish (NFE) AF: 0.657 AC: 44698 AN: 67998

Other (OTH) AF: 0.620 AC: 1310 AN: 2114

Alfa AF: 0.641 Hom.: 6269

Bravo AF: 0.612

Asia WGS AF: 0.669 AC: 2329 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.26
PhyloP100		0.043
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: rs1213026; hg19: chr13-110819362; COSMIC: COSV65429020; COSMIC: COSV65429020;