2-227022057-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000092.5(COL4A4):c.4207T>C(p.Ser1403Pro) variant causes a missense change. The variant allele was found at a frequency of 0.447 in 1,612,828 control chromosomes in the GnomAD database, including 164,328 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 19177 hom., cov: 31)

Exomes 𝑓: 0.44 ( 145151 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.74

Variant links:

Genes affected

COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

COL4A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.318786E-5).

BP6

Variant 2-227022057-A-G is Benign according to our data. Variant chr2-227022057-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 255038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227022057-A-G is described in Lovd as [Benign]. Variant chr2-227022057-A-G is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.623 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL4A4	NM_000092.5 link	c.4207T>C	p.Ser1403Pro	missense_variant	Exon 44 of 48	ENST00000396625.5	NP_000083.3	P53420

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 link	c.4207T>C	p.Ser1403Pro	missense_variant	Exon 44 of 48	5	NM_000092.5	ENSP00000379866.3		P53420

Frequencies

GnomAD3 genomes

AF:

0.494

AC:

74967

AN:

151788

Hom.:

19134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.629

Gnomad AMI

AF:

0.404

Gnomad AMR

AF:

0.480

Gnomad ASJ

AF:

0.493

Gnomad EAS

AF:

0.388

Gnomad SAS

AF:

0.550

Gnomad FIN

AF:

0.489

Gnomad MID

AF:

0.424

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.459

GnomAD3 exomes

AF:

0.477

AC:

118999

AN:

249310

Hom.:

29113

AF XY:

0.473

AC XY:

64022

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.642

Gnomad AMR exome

AF:

0.538

Gnomad ASJ exome

AF:

0.509

Gnomad EAS exome

AF:

0.396

Gnomad SAS exome

AF:

0.559

Gnomad FIN exome

AF:

0.496

Gnomad NFE exome

AF:

0.422

Gnomad OTH exome

AF:

0.457

GnomAD4 exome

AF:

0.442

AC:

645388

AN:

1460922

Hom.:

145151

Cov.:

AF XY:

0.443

AC XY:

322051

AN XY:

726778

show subpopulations

Gnomad4 AFR exome

AF:

0.637

Gnomad4 AMR exome

AF:

0.533

Gnomad4 ASJ exome

AF:

0.515

Gnomad4 EAS exome

AF:

0.411

Gnomad4 SAS exome

AF:

0.559

Gnomad4 FIN exome

AF:

0.495

Gnomad4 NFE exome

AF:

0.420

Gnomad4 OTH exome

AF:

0.449

GnomAD4 genome

AF:

0.494

AC:

75056

AN:

151906

Hom.:

19177

Cov.:

AF XY:

0.494

AC XY:

36664

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.630

Gnomad4 AMR

AF:

0.480

Gnomad4 ASJ

AF:

0.493

Gnomad4 EAS

AF:

0.388

Gnomad4 SAS

AF:

0.550

Gnomad4 FIN

AF:

0.489

Gnomad4 NFE

AF:

0.422

Gnomad4 OTH

AF:

0.453

Alfa

AF:

0.433

Hom.:

36233

Bravo

AF:

0.500

TwinsUK

AF:

0.421

AC:

1560

ALSPAC

AF:

0.415

AC:

1598

ESP6500AA

AF:

0.608

AC:

2276

ESP6500EA

AF:

0.419

AC:

3440

ExAC

AF:

0.476

AC:

57469

Asia WGS

AF:

0.483

AC:

1682

AN:

3478

EpiCase

AF:

0.401

EpiControl

AF:

0.407

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 70% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 65. Only high quality variants are reported. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 21, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Ser1403Pro in exon 44 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 68.91% (911/1322) of African chr omosomes by the 1000 Genomes Project (Phase 3; dbSNP rs3752895). -

Nov 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

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. -

not provided

Benign:3

Apr 03, 2017

Athena Diagnostics

Significance: 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Alport syndrome

Benign:2

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 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. -

Autosomal recessive Alport syndrome

Benign:1

Jul 10, 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

AlphaMissense

Benign

0.043

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.33

DEOGEN2

Benign

0.060

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.42

MetaRNN

Benign

0.000073

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-2.0

PrimateAI

Benign

0.42

PROVEAN

Benign

3.2

REVEL

Benign

0.23

Sift

Benign

0.78

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.071

MPC

0.18

ClinPred

0.0068

GERP RS

5.6

Varity_R

0.066

gMVP

0.18

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