NM_001845.6:c.1121-58A>G

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.1121-58A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.276 in 1,600,012 control chromosomes in the GnomAD database, including 63,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7526 hom., cov: 33)

Exomes 𝑓: 0.27 ( 56054 hom. )

Consequence

COL4A1
NM_001845.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.328

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=-0.95).

BP6

Variant 13-110198689-T-C is Benign according to our data. Variant chr13-110198689-T-C is described in ClinVar as Benign. ClinVar VariationId is 1229399.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.1121-58A>G		intron_variant	Intron 20 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.1121-58A>G		intron_variant	Intron 20 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.1121-58A>G		intron_variant	Intron 20 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.306

AC:

46490

AN:

152006

Hom.:

7496

Cov.:

show subpopulations

Gnomad AFR

AF:

0.380

Gnomad AMI

AF:

0.0735

Gnomad AMR

AF:

0.335

Gnomad ASJ

AF:

0.255

Gnomad EAS

AF:

0.103

Gnomad SAS

AF:

0.216

Gnomad FIN

AF:

0.332

Gnomad MID

AF:

0.259

Gnomad NFE

AF:

0.279

Gnomad OTH

AF:

0.264

GnomAD4 exome

AF:

0.273

AC:

395558

AN:

1447888

Hom.:

56054

AF XY:

0.272

AC XY:

195904

AN XY:

721090

show subpopulations

African (AFR)

AF:

0.390

AC:

12970

AN:

33214

American (AMR)

AF:

0.346

AC:

15430

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.253

AC:

6574

AN:

26032

East Asian (EAS)

AF:

0.0736

AC:

2917

AN:

39634

South Asian (SAS)

AF:

0.235

AC:

20136

AN:

85788

European-Finnish (FIN)

AF:

0.328

AC:

17088

AN:

52132

Middle Eastern (MID)

AF:

0.266

AC:

1528

AN:

5746

European-Non Finnish (NFE)

AF:

0.275

AC:

302840

AN:

1100730

Other (OTH)

AF:

0.268

AC:

16075

AN:

59968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

15004

30008

45011

60015

75019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10072

20144

30216

40288

50360

<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:

0.306

AC:

46576

AN:

152124

Hom.:

7526

Cov.:

AF XY:

0.306

AC XY:

22768

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.381

AC:

15783

AN:

41472

American (AMR)

AF:

0.335

AC:

5124

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.255

AC:

885

AN:

3466

East Asian (EAS)

AF:

0.103

AC:

533

AN:

5178

South Asian (SAS)

AF:

0.216

AC:

1042

AN:

4818

European-Finnish (FIN)

AF:

0.332

AC:

3516

AN:

10592

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.279

AC:

18980

AN:

67994

Other (OTH)

AF:

0.269

AC:

568

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1631

3263

4894

6526

8157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

452

904

1356

1808

2260

<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:

0.277

Hom.:

8109

Bravo

AF:

0.307

Asia WGS

AF:

0.212

AC:

738

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 26, 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

-0.95

CADD

Benign

4.4

(source)

DANN

Benign

0.58

PhyloP100

-0.33

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