chr13-110166251-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_001845.6(COL4A1):c.4002A>C(p.Gln1334His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,606,430 control chromosomes in the GnomAD database, including 88,279 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7518 hom., cov: 32)

Exomes 𝑓: 0.33 ( 80761 hom. )

Consequence

COL4A1
NM_001845.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 0.718

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the COL4A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 194 curated pathogenic missense variants (we use a threshold of 10). The gene has 77 curated benign missense variants. Gene score misZ: 3.0194 (below the threshold of 3.09). Trascript score misZ: 4.972 (above the threshold of 3.09). GenCC associations: The gene is linked to brain small vessel disease 1 with or without ocular anomalies, pontine autosomal dominant microangiopathy with leukoencephalopathy, muscular dystrophy-dystroglycanopathy, type A, microangiopathy and leukoencephalopathy, pontine, autosomal dominant, familial porencephaly, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, retinal arterial tortuosity.

BP4

Computational evidence support a benign effect (MetaRNN=0.013116002).

BP6

Variant 13-110166251-T-G is Benign according to our data. Variant chr13-110166251-T-G is described in ClinVar as [Benign]. Clinvar id is 197520.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-110166251-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A1	NM_001845.6 link	c.4002A>C	p.Gln1334His	missense_variant	Exon 45 of 52	ENST00000375820.10	NP_001836.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A1	ENST00000375820.10 link	c.4002A>C	p.Gln1334His	missense_variant	Exon 45 of 52	1	NM_001845.6	ENSP00000364979.4		P02462-1
COL4A1	ENST00000650424.1 link	c.156A>C	p.Gln52His	missense_variant	Exon 3 of 10			ENSP00000497477.2		A0A3B3ISV3

Frequencies

GnomAD3 genomes

AF:

0.311

AC:

47236

AN:

151996

Hom.:

7517

Cov.:

show subpopulations

Gnomad AFR

AF:

0.280

Gnomad AMI

AF:

0.542

Gnomad AMR

AF:

0.265

Gnomad ASJ

AF:

0.399

Gnomad EAS

AF:

0.239

Gnomad SAS

AF:

0.311

Gnomad FIN

AF:

0.268

Gnomad MID

AF:

0.377

Gnomad NFE

AF:

0.343

Gnomad OTH

AF:

0.337

GnomAD3 exomes

AF:

0.304

AC:

76506

AN:

251484

Hom.:

12296

AF XY:

0.313

AC XY:

42501

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.284

Gnomad AMR exome

AF:

0.181

Gnomad ASJ exome

AF:

0.393

Gnomad EAS exome

AF:

0.253

Gnomad SAS exome

AF:

0.338

Gnomad FIN exome

AF:

0.261

Gnomad NFE exome

AF:

0.342

Gnomad OTH exome

AF:

0.339

GnomAD4 exome

AF:

0.330

AC:

479380

AN:

1454316

Hom.:

80761

Cov.:

AF XY:

0.331

AC XY:

239763

AN XY:

724036

show subpopulations

Gnomad4 AFR exome

AF:

0.280

Gnomad4 AMR exome

AF:

0.193

Gnomad4 ASJ exome

AF:

0.391

Gnomad4 EAS exome

AF:

0.257

Gnomad4 SAS exome

AF:

0.334

Gnomad4 FIN exome

AF:

0.266

Gnomad4 NFE exome

AF:

0.340

Gnomad4 OTH exome

AF:

0.325

GnomAD4 genome

AF:

0.311

AC:

47251

AN:

152114

Hom.:

7518

Cov.:

AF XY:

0.306

AC XY:

22776

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.264

Gnomad4 ASJ

AF:

0.399

Gnomad4 EAS

AF:

0.239

Gnomad4 SAS

AF:

0.313

Gnomad4 FIN

AF:

0.268

Gnomad4 NFE

AF:

0.343

Gnomad4 OTH

AF:

0.334

Alfa

AF:

0.335

Hom.:

22371

Bravo

AF:

0.305

TwinsUK

AF:

0.339

AC:

1256

ALSPAC

AF:

0.342

AC:

1319

ESP6500AA

AF:

0.282

AC:

1243

ESP6500EA

AF:

0.341

AC:

2935

ExAC

AF:

0.310

AC:

37612

Asia WGS

AF:

0.259

AC:

901

AN:

3478

EpiCase

AF:

0.353

EpiControl

AF:

0.355

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jan 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 15, 2014

Eurofins Ntd Llc (ga)

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

- -

Brain small vessel disease 1 with or without ocular anomalies

Benign:3

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 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 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

Benign:2

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided

Benign:2

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

- -

Porencephalic cyst

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.38

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.81

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.50

MetaRNN

Benign

0.013

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.0

REVEL

Uncertain

0.34

Sift

Benign

0.12

Sift4G

Benign

0.12

Polyphen

0.26

Vest4

0.055

MutPred

0.25

Gain of catalytic residue at D1330 (P = 0);

MPC

0.59

ClinPred

0.019

GERP RS

-1.2

Varity_R

0.067

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over