rs1133219

Variant names:

Your query was ambiguous. Multiple possible variants found:

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.4470C>T(p.Ala1490Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,610,064 control chromosomes in the GnomAD database, including 100,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 9528 hom., cov: 34)

Exomes 𝑓: 0.35 ( 90952 hom. )

Consequence

COL4A1
NM_001845.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -2.54

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=-0.68).

BP6

Variant 13-110161362-G-A is Benign according to our data. Variant chr13-110161362-G-A is described in ClinVar as Benign. ClinVar VariationId is 258255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.54 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.362 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.4470C>T	p.Ala1490Ala	synonymous	Exon 49 of 52	NP_001836.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL4A1	ENST00000375820.10	TSL:1 MANE Select	c.4470C>T	p.Ala1490Ala	synonymous	Exon 49 of 52	ENSP00000364979.4
COL4A1	ENST00000650424.2		c.4470C>T	p.Ala1490Ala	synonymous	Exon 49 of 52	ENSP00000497477.2
COL4A1	ENST00000615732.3	TSL:5	c.4278C>T	p.Ala1426Ala	synonymous	Exon 49 of 52	ENSP00000478222.3

Frequencies

GnomAD3 genomes

AF:

0.351

AC:

53295

AN:

152048

Hom.:

9519

Cov.:

show subpopulations

Gnomad AFR

AF:

0.368

Gnomad AMI

AF:

0.352

Gnomad AMR

AF:

0.255

Gnomad ASJ

AF:

0.342

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.439

Gnomad MID

AF:

0.310

Gnomad NFE

AF:

0.360

Gnomad OTH

AF:

0.341

GnomAD2 exomes

AF:

0.334

AC:

81567

AN:

244350

AF XY:

0.341

show subpopulations

Gnomad AFR exome

AF:

0.366

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.352

Gnomad EAS exome

AF:

0.205

Gnomad FIN exome

AF:

0.430

Gnomad NFE exome

AF:

0.356

Gnomad OTH exome

AF:

0.330

GnomAD4 exome

AF:

0.351

AC:

511446

AN:

1457898

Hom.:

90952

Cov.:

AF XY:

0.353

AC XY:

255815

AN XY:

724908

show subpopulations

African (AFR)

AF:

0.366

AC:

12227

AN:

33426

American (AMR)

AF:

0.215

AC:

9483

AN:

44056

Ashkenazi Jewish (ASJ)

AF:

0.346

AC:

9027

AN:

26074

East Asian (EAS)

AF:

0.201

AC:

7971

AN:

39610

South Asian (SAS)

AF:

0.381

AC:

32753

AN:

85902

European-Finnish (FIN)

AF:

0.425

AC:

22550

AN:

53030

Middle Eastern (MID)

AF:

0.361

AC:

2082

AN:

5762

European-Non Finnish (NFE)

AF:

0.355

AC:

394462

AN:

1109792

Other (OTH)

AF:

0.347

AC:

20891

AN:

60246

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

18423

36845

55268

73690

92113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12466

24932

37398

49864

62330

<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:

0.350

AC:

53328

AN:

152166

Hom.:

9528

Cov.:

AF XY:

0.352

AC XY:

26191

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.367

AC:

15240

AN:

41508

American (AMR)

AF:

0.255

AC:

3897

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.342

AC:

1187

AN:

3466

East Asian (EAS)

AF:

0.196

AC:

1014

AN:

5178

South Asian (SAS)

AF:

0.360

AC:

1737

AN:

4826

European-Finnish (FIN)

AF:

0.439

AC:

4637

AN:

10574

Middle Eastern (MID)

AF:

0.310

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.360

AC:

24476

AN:

68002

Other (OTH)

AF:

0.345

AC:

729

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1826

3651

5477

7302

9128

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

530

1060

1590

2120

2650

<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:

0.350

Hom.:

31306

Bravo

AF:

0.330

Asia WGS

AF:

0.297

AC:

1036

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (2)

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

not provided (2)

Porencephalic cyst (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.4

(source)

DANN

Benign

0.37

PhyloP100

-2.5

Mutation Taster

=94/6

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over