13-110174532-GA-GAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001845.6(COL4A1):c.3326-7dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,613,980 control chromosomes in the GnomAD database, including 22 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 21 hom. )

Consequence

COL4A1
NM_001845.6 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.78

Publications

0 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 -16 ACMG points.

BP6

Variant 13-110174532-G-GA is Benign according to our data. Variant chr13-110174532-G-GA is described in ClinVar as [Likely_benign]. Clinvar id is 311040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00228 (347/152124) while in subpopulation NFE AF = 0.00372 (253/67984). AF 95% confidence interval is 0.00334. There are 1 homozygotes in GnomAd4. There are 166 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.3326-7dupT		splice_region_variant, intron_variant	Intron 38 of 51	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.3326-7_3326-6insT		splice_region_variant, intron_variant	Intron 38 of 51	1	NM_001845.6	ENSP00000364979.4		P02462-1

Frequencies

GnomAD3 genomes

AF:

0.00228

AC:

347

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000508

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00397

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00372

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00248

AC:

624

AN:

251338

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00427

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00457

Gnomad NFE exome

AF:

0.00369

Gnomad OTH exome

AF:

0.00310

GnomAD4 exome

AF:

0.00321

AC:

4696

AN:

1461856

Hom.:

Cov.:

AF XY:

0.00310

AC XY:

2258

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33478

American (AMR)

AF:

0.000559

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00432

AC:

113

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000661

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00395

AC:

211

AN:

53404

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00370

AC:

4109

AN:

1112002

Other (OTH)

AF:

0.00262

AC:

158

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

277

554

832

1109

1386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00228

AC:

347

AN:

152124

Hom.:

Cov.:

AF XY:

0.00223

AC XY:

166

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.000506

AC:

AN:

41496

American (AMR)

AF:

0.000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00397

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00372

AC:

253

AN:

67984

Other (OTH)

AF:

0.00331

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00319

Hom.:

Bravo

AF:

0.00216

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00300

EpiControl

AF:

0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL4A1: BP4, BS2 -

Aug 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2024

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

not specified

Benign:1

Nov 16, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

COL4A1-related disorder

Benign:1

Feb 08, 2022

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Brain small vessel disease 1 with or without ocular anomalies

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Porencephalic cyst

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Retinal arterial tortuosity;C2673195:Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome;C3281105:Hemorrhage, intracerebral, susceptibility to;C4551998:Brain small vessel disease 1 with or without ocular anomalies;C5231411:Microangiopathy and leukoencephalopathy, pontine, autosomal dominant

Benign:1

Aug 09, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.8

Mutation Taster

=100/0

polymorphism

(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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13-110174532-GA-GAA

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