13-110203747-A-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.958-140T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 854,052 control chromosomes in the GnomAD database, including 3,627 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 2415 hom., cov: 34)

Exomes 𝑓: 0.026 ( 1212 hom. )

Consequence

COL4A1
NM_001845.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.391

Publications

4 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=-0.83).

BP6

Variant 13-110203747-A-T is Benign according to our data. Variant chr13-110203747-A-T is described in ClinVar as Benign. ClinVar VariationId is 1295700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.958-140T>A		intron_variant	Intron 17 of 51	ENST00000375820.10	NP_001836.3
COL4A1	NM_001303110.2 link	c.958-140T>A		intron_variant	Intron 17 of 24		NP_001290039.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.958-140T>A		intron_variant	Intron 17 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16394

AN:

152138

Hom.:

2394

Cov.:

show subpopulations

Gnomad AFR

AF:

0.338

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0502

Gnomad ASJ

AF:

0.00864

Gnomad EAS

AF:

0.0630

Gnomad SAS

AF:

0.0112

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0414

Gnomad NFE

AF:

0.0151

Gnomad OTH

AF:

0.0856

GnomAD4 exome

AF:

0.0255

AC:

17899

AN:

701794

Hom.:

1212

AF XY:

0.0234

AC XY:

8637

AN XY:

369478

show subpopulations

African (AFR)

AF:

0.335

AC:

6011

AN:

17934

American (AMR)

AF:

0.0326

AC:

1089

AN:

33410

Ashkenazi Jewish (ASJ)

AF:

0.0114

AC:

221

AN:

19330

East Asian (EAS)

AF:

0.0479

AC:

1629

AN:

33994

South Asian (SAS)

AF:

0.00843

AC:

527

AN:

62500

European-Finnish (FIN)

AF:

0.00252

AC:

104

AN:

41264

Middle Eastern (MID)

AF:

0.0536

AC:

207

AN:

3860

European-Non Finnish (NFE)

AF:

0.0144

AC:

6555

AN:

454502

Other (OTH)

AF:

0.0445

AC:

1556

AN:

35000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

728

1456

2184

2912

3640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

224

448

672

896

1120

<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:

0.108

AC:

16461

AN:

152258

Hom.:

2415

Cov.:

AF XY:

0.103

AC XY:

7651

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.338

AC:

14040

AN:

41510

American (AMR)

AF:

0.0500

AC:

765

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00864

AC:

AN:

3472

East Asian (EAS)

AF:

0.0636

AC:

330

AN:

5192

South Asian (SAS)

AF:

0.0106

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0150

AC:

1023

AN:

68032

Other (OTH)

AF:

0.0922

AC:

195

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

617

1235

1852

2470

3087

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

150

300

450

600

750

<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:

0.0686

Hom.:

178

Bravo

AF:

0.122

Asia WGS

AF:

0.0920

AC:

319

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

- -

Jul 09, 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

-0.83

CADD

Benign

0.34

(source)

DANN

Benign

0.51

PhyloP100

0.39

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