rs36121515

Positions:

chr2-227059512-G-A

Variant summary

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

The NM_000092.5(COL4A4):c.2276C>T(p.Pro759Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00483 in 1,614,026 control chromosomes in the GnomAD database, including 323 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 182 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 141 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 3.57

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=0.006734222).

BP6

Variant 2-227059512-G-A is Benign according to our data. Variant chr2-227059512-G-A is described in ClinVar as [Benign]. Clinvar id is 255019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227059512-G-A is described in Lovd as [Benign]. Variant chr2-227059512-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A4	NM_000092.5 linkuse as main transcript	c.2276C>T	p.Pro759Leu	missense_variant	28/48	ENST00000396625.5	NP_000083.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A4	ENST00000396625.5 linkuse as main transcript	c.2276C>T	p.Pro759Leu	missense_variant	28/48	5	NM_000092.5	ENSP00000379866	P1

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3807

AN:

152052

Hom.:

182

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0873

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00727

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.00652

AC:

1628

AN:

249558

Hom.:

AF XY:

0.00493

AC XY:

667

AN XY:

135396

show subpopulations

Gnomad AFR exome

AF:

0.0915

Gnomad AMR exome

AF:

0.00403

Gnomad ASJ exome

AF:

0.000199

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000450

Gnomad OTH exome

AF:

0.00297

GnomAD4 exome

AF:

0.00272

AC:

3982

AN:

1461856

Hom.:

141

Cov.:

AF XY:

0.00236

AC XY:

1719

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0903

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000209

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.00560

GnomAD4 genome

AF:

0.0251

AC:

3817

AN:

152170

Hom.:

182

Cov.:

AF XY:

0.0234

AC XY:

1743

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0873

Gnomad4 AMR

AF:

0.00719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.00581

Hom.:

Bravo

AF:

0.0283

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0841

AC:

308

ESP6500EA

AF:

0.000614

AC:

ExAC

AF:

0.00776

AC:

937

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2017	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro759Leu in exon 28 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 8.87% (867/9776) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs36121515). -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 12, 2019	- -

Alport syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Aug 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.23

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.40

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

0.98

D;D

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.39

Sift

Uncertain

0.014

Sift4G

Uncertain

0.012

Polyphen

0.91

Vest4

0.37

MVP

0.77

MPC

0.58

ClinPred

0.055

GERP RS

5.1

Varity_R

0.13

gMVP

0.28

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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