rs874203

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001845.6(COL4A1):c.3189A>T(p.Arg1063Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,613,290 control chromosomes in the GnomAD database, including 105,546 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 8757 hom., cov: 33)

Exomes 𝑓: 0.36 ( 96789 hom. )

Consequence

COL4A1
NM_001845.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.671

Publications

22 publications found

Variant links:

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

COL4A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 13-110175227-T-A is Benign according to our data. Variant chr13-110175227-T-A is described in ClinVar as Benign. ClinVar VariationId is 258251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.671 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.365 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL4A1	NM_001845.6	MANE Select	c.3189A>T	p.Arg1063Arg	synonymous	Exon 37 of 52	NP_001836.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.3189A>T	p.Arg1063Arg	synonymous	Exon 37 of 52	ENSP00000364979.4
COL4A1	ENST00000650424.2		c.3189A>T	p.Arg1063Arg	synonymous	Exon 37 of 52	ENSP00000497477.2
COL4A1	ENST00000933608.1		c.3189A>T	p.Arg1063Arg	synonymous	Exon 37 of 51	ENSP00000603667.1

Frequencies

GnomAD3 genomes

AF:

0.339

AC:

51446

AN:

151810

Hom.:

8743

Cov.:

show subpopulations

Gnomad AFR

AF:

0.276

Gnomad AMI

AF:

0.561

Gnomad AMR

AF:

0.361

Gnomad ASJ

AF:

0.340

Gnomad EAS

AF:

0.294

Gnomad SAS

AF:

0.360

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.297

Gnomad NFE

AF:

0.369

Gnomad OTH

AF:

0.351

GnomAD2 exomes

AF:

0.354

AC:

88877

AN:

251100

AF XY:

0.355

show subpopulations

Gnomad AFR exome

AF:

0.278

Gnomad AMR exome

AF:

0.392

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.297

Gnomad FIN exome

AF:

0.352

Gnomad NFE exome

AF:

0.363

Gnomad OTH exome

AF:

0.350

GnomAD4 exome

AF:

0.362

AC:

528802

AN:

1461362

Hom.:

96789

Cov.:

AF XY:

0.362

AC XY:

263210

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.268

AC:

8977

AN:

33472

American (AMR)

AF:

0.391

AC:

17471

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

8311

AN:

26128

East Asian (EAS)

AF:

0.265

AC:

10522

AN:

39698

South Asian (SAS)

AF:

0.365

AC:

31439

AN:

86244

European-Finnish (FIN)

AF:

0.356

AC:

19031

AN:

53390

Middle Eastern (MID)

AF:

0.263

AC:

1514

AN:

5766

European-Non Finnish (NFE)

AF:

0.369

AC:

410178

AN:

1111566

Other (OTH)

AF:

0.354

AC:

21359

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

20162

40325

60487

80650

100812

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12966

25932

38898

51864

64830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.339

AC:

51498

AN:

151928

Hom.:

8757

Cov.:

AF XY:

0.339

AC XY:

25173

AN XY:

74250

show subpopulations

African (AFR)

AF:

0.276

AC:

11458

AN:

41478

American (AMR)

AF:

0.361

AC:

5511

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.340

AC:

1177

AN:

3466

East Asian (EAS)

AF:

0.295

AC:

1519

AN:

5154

South Asian (SAS)

AF:

0.361

AC:

1744

AN:

4826

European-Finnish (FIN)

AF:

0.351

AC:

3706

AN:

10548

Middle Eastern (MID)

AF:

0.292

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.369

AC:

25042

AN:

67890

Other (OTH)

AF:

0.356

AC:

750

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1817

3633

5450

7266

9083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

526

1052

1578

2104

2630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.352

Hom.:

3195

Bravo

AF:

0.337

Asia WGS

AF:

0.355

AC:

1234

AN:

3478

EpiCase

AF:

0.355

EpiControl

AF:

0.352

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Brain small vessel disease 1 with or without ocular anomalies (2)

not provided (2)

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.020

(source)

DANN

Benign

0.44

PhyloP100

-0.67

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over