13-110209956-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001845.6(COL4A1):c.615+24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,611,612 control chromosomes in the GnomAD database, including 53,456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.24 ( 4616 hom., cov: 32)

Exomes 𝑓: 0.25 ( 48840 hom. )

Consequence

COL4A1
NM_001845.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.252

Publications

9 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 13-110209956-G-A is Benign according to our data. Variant chr13-110209956-G-A is described in ClinVar as Benign. ClinVar VariationId is 1227525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.303 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.615+24C>T		intron_variant	Intron 10 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.615+24C>T		intron_variant	Intron 10 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.615+24C>T		intron_variant	Intron 10 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.236

AC:

35826

AN:

151916

Hom.:

4613

Cov.:

show subpopulations

Gnomad AFR

AF:

0.169

Gnomad AMI

AF:

0.0648

Gnomad AMR

AF:

0.310

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.0468

Gnomad SAS

AF:

0.213

Gnomad FIN

AF:

0.322

Gnomad MID

AF:

0.239

Gnomad NFE

AF:

0.265

Gnomad OTH

AF:

0.211

GnomAD2 exomes

AF:

0.247

AC:

61989

AN:

251132

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.166

Gnomad AMR exome

AF:

0.326

Gnomad ASJ exome

AF:

0.238

Gnomad EAS exome

AF:

0.0407

Gnomad FIN exome

AF:

0.315

Gnomad NFE exome

AF:

0.262

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.253

AC:

368965

AN:

1459578

Hom.:

48840

Cov.:

AF XY:

0.253

AC XY:

183404

AN XY:

726262

show subpopulations

African (AFR)

AF:

0.166

AC:

5568

AN:

33450

American (AMR)

AF:

0.327

AC:

14640

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.239

AC:

6243

AN:

26122

East Asian (EAS)

AF:

0.0322

AC:

1279

AN:

39690

South Asian (SAS)

AF:

0.229

AC:

19770

AN:

86232

European-Finnish (FIN)

AF:

0.313

AC:

16705

AN:

53388

Middle Eastern (MID)

AF:

0.250

AC:

1440

AN:

5766

European-Non Finnish (NFE)

AF:

0.260

AC:

289012

AN:

1109874

Other (OTH)

AF:

0.237

AC:

14308

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

13831

27662

41494

55325

69156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9606

19212

28818

38424

48030

<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:

0.236

AC:

35850

AN:

152034

Hom.:

4616

Cov.:

AF XY:

0.239

AC XY:

17762

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.168

AC:

6984

AN:

41468

American (AMR)

AF:

0.310

AC:

4741

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.244

AC:

847

AN:

3466

East Asian (EAS)

AF:

0.0465

AC:

240

AN:

5162

South Asian (SAS)

AF:

0.213

AC:

1023

AN:

4808

European-Finnish (FIN)

AF:

0.322

AC:

3399

AN:

10568

Middle Eastern (MID)

AF:

0.247

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.265

AC:

18045

AN:

67974

Other (OTH)

AF:

0.209

AC:

440

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1405

2810

4215

5620

7025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

374

748

1122

1496

1870

<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:

0.252

Hom.:

2266

Bravo

AF:

0.228

Asia WGS

AF:

0.125

AC:

435

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 29, 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

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.18

(source)

DANN

Benign

0.47

PhyloP100

-0.25

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over