13-110207396-C-T

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.780+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.632 in 1,607,206 control chromosomes in the GnomAD database, including 325,232 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 26153 hom., cov: 32)

Exomes 𝑓: 0.64 ( 299079 hom. )

Consequence

COL4A1
NM_001845.6 splice_region, intron

Scores

Splicing: ADA: 0.000007063

Clinical Significance

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

Conservation

PhyloP100: -3.17

Publications

19 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=-0.91).

BP6

Variant 13-110207396-C-T is Benign according to our data. Variant chr13-110207396-C-T is described in ClinVar as Benign. ClinVar VariationId is 258262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.780+7G>A		splice_region_variant, intron_variant	Intron 13 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.780+7G>A		splice_region_variant, intron_variant	Intron 13 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.780+7G>A		splice_region_variant, intron_variant	Intron 13 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.577

AC:

87531

AN:

151794

Hom.:

26156

Cov.:

show subpopulations

Gnomad AFR

AF:

0.422

Gnomad AMI

AF:

0.877

Gnomad AMR

AF:

0.545

Gnomad ASJ

AF:

0.699

Gnomad EAS

AF:

0.759

Gnomad SAS

AF:

0.700

Gnomad FIN

AF:

0.610

Gnomad MID

AF:

0.642

Gnomad NFE

AF:

0.638

Gnomad OTH

AF:

0.622

GnomAD2 exomes

AF:

0.620

AC:

155997

AN:

251422

AF XY:

0.632

show subpopulations

Gnomad AFR exome

AF:

0.414

Gnomad AMR exome

AF:

0.496

Gnomad ASJ exome

AF:

0.702

Gnomad EAS exome

AF:

0.757

Gnomad FIN exome

AF:

0.606

Gnomad NFE exome

AF:

0.642

Gnomad OTH exome

AF:

0.641

GnomAD4 exome

AF:

0.638

AC:

928192

AN:

1455294

Hom.:

299079

Cov.:

AF XY:

0.641

AC XY:

464145

AN XY:

724398

show subpopulations

African (AFR)

AF:

0.402

AC:

13421

AN:

33362

American (AMR)

AF:

0.498

AC:

22279

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.704

AC:

18367

AN:

26104

East Asian (EAS)

AF:

0.772

AC:

30619

AN:

39676

South Asian (SAS)

AF:

0.684

AC:

58886

AN:

86124

European-Finnish (FIN)

AF:

0.607

AC:

32396

AN:

53410

Middle Eastern (MID)

AF:

0.660

AC:

3796

AN:

5754

European-Non Finnish (NFE)

AF:

0.642

AC:

709970

AN:

1106006

Other (OTH)

AF:

0.639

AC:

38458

AN:

60154

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

16481

32962

49442

65923

82404

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18664

37328

55992

74656

93320

<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:

0.576

AC:

87543

AN:

151912

Hom.:

26153

Cov.:

AF XY:

0.578

AC XY:

42919

AN XY:

74238

show subpopulations

African (AFR)

AF:

0.422

AC:

17458

AN:

41394

American (AMR)

AF:

0.544

AC:

8309

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.699

AC:

2427

AN:

3470

East Asian (EAS)

AF:

0.758

AC:

3902

AN:

5146

South Asian (SAS)

AF:

0.700

AC:

3372

AN:

4816

European-Finnish (FIN)

AF:

0.610

AC:

6425

AN:

10528

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.638

AC:

43360

AN:

67974

Other (OTH)

AF:

0.619

AC:

1304

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1774

3547

5321

7094

8868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

742

1484

2226

2968

3710

<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:

0.626

Hom.:

44336

Bravo

AF:

0.565

Asia WGS

AF:

0.684

AC:

2380

AN:

3478

EpiCase

AF:

0.656

EpiControl

AF:

0.660

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 02, 2021

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Mar 03, 2015

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

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 22, 2021

Genome-Nilou Lab

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

-0.91

CADD

Benign

0.059

(source)

DANN

Benign

0.38

PhyloP100

-3.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000071

dbscSNV1_RF

Benign

0.0

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