2-227246719-T-C

Position:

chr2-227246719-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000091.5(COL4A3):c.422T>C(p.Leu141Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 1,610,764 control chromosomes in the GnomAD database, including 560,578 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar.

Frequency

Genomes: 𝑓 0.78 ( 46853 hom., cov: 30)

Exomes 𝑓: 0.84 ( 513725 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.487

Variant links:

Genes affected

COL4A3 (HGNC:2204): (collagen type IV alpha 3 chain) Type IV collagen, the major structural component of basement membranes, is a multimeric protein composed of 3 alpha subunits. These subunits are encoded by 6 different genes, alpha 1 through alpha 6, each of which can form a triple helix structure with 2 other subunits to form type IV collagen. This gene encodes alpha 3. In the Goodpasture syndrome, autoantibodies bind to the collagen molecules in the basement membranes of alveoli and glomeruli. The epitopes that elicit these autoantibodies are localized largely to the non-collagenous C-terminal domain of the protein. A specific kinase phosphorylates amino acids in this same C-terminal region and the expression of this kinase is upregulated during pathogenesis. This gene is also linked to an autosomal recessive form of Alport syndrome. The mutations contributing to this syndrome are also located within the exons that encode this C-terminal region. 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. [provided by RefSeq, Jun 2010]

COL4A3 links:

MFF-DT (HGNC:41067): (MFF divergent transcript)

MFF-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_000091.5

BP4

Computational evidence support a benign effect (MetaRNN=4.154798E-6).

BP6

Variant 2-227246719-T-C is Benign according to our data. Variant chr2-227246719-T-C is described in ClinVar as [Benign]. Clinvar id is 254996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227246719-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.885 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.422T>C	p.Leu141Pro	missense_variant	7/52	ENST00000396578.8
MFF-DT	NR_102371.1 linkuse as main transcript	n.1593-8545A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.422T>C	p.Leu141Pro	missense_variant	7/52	1	NM_000091.5	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.1593-8545A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.780

AC:

118416

AN:

151884

Hom.:

46823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.626

Gnomad AMI

AF:

0.791

Gnomad AMR

AF:

0.847

Gnomad ASJ

AF:

0.779

Gnomad EAS

AF:

0.907

Gnomad SAS

AF:

0.861

Gnomad FIN

AF:

0.818

Gnomad MID

AF:

0.623

Gnomad NFE

AF:

0.837

Gnomad OTH

AF:

0.777

GnomAD3 exomes

AF:

0.834

AC:

207949

AN:

249198

Hom.:

87403

AF XY:

0.836

AC XY:

113091

AN XY:

135196

show subpopulations

Gnomad AFR exome

AF:

0.628

Gnomad AMR exome

AF:

0.887

Gnomad ASJ exome

AF:

0.775

Gnomad EAS exome

AF:

0.919

Gnomad SAS exome

AF:

0.857

Gnomad FIN exome

AF:

0.825

Gnomad NFE exome

AF:

0.835

Gnomad OTH exome

AF:

0.822

GnomAD4 exome

AF:

0.838

AC:

1222544

AN:

1458760

Hom.:

513725

Cov.:

AF XY:

0.838

AC XY:

608237

AN XY:

725874

show subpopulations

Gnomad4 AFR exome

AF:

0.622

Gnomad4 AMR exome

AF:

0.881

Gnomad4 ASJ exome

AF:

0.775

Gnomad4 EAS exome

AF:

0.890

Gnomad4 SAS exome

AF:

0.857

Gnomad4 FIN exome

AF:

0.826

Gnomad4 NFE exome

AF:

0.843

Gnomad4 OTH exome

AF:

0.826

GnomAD4 genome

AF:

0.780

AC:

118499

AN:

152004

Hom.:

46853

Cov.:

AF XY:

0.780

AC XY:

57977

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.626

Gnomad4 AMR

AF:

0.847

Gnomad4 ASJ

AF:

0.779

Gnomad4 EAS

AF:

0.907

Gnomad4 SAS

AF:

0.861

Gnomad4 FIN

AF:

0.818

Gnomad4 NFE

AF:

0.837

Gnomad4 OTH

AF:

0.776

Alfa

AF:

0.825

Hom.:

127636

Bravo

AF:

0.775

TwinsUK

AF:

0.829

AC:

3075

ALSPAC

AF:

0.846

AC:

3260

ESP6500AA

AF:

0.643

AC:

2369

ESP6500EA

AF:

0.828

AC:

6759

ExAC

AF:

0.830

AC:

100213

Asia WGS

AF:

0.847

AC:

2947

AN:

3478

EpiCase

AF:

0.823

EpiControl

AF:

0.829

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Leu141Pro in exon 7 of COL4A3: This variant is not expected to have clinical s ignificance because it has been identified in 91.36% (7855/8598) of East Asian c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org; dbSNP rs10178458). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 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	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 95% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 88. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Autosomal recessive Alport syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 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	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Autosomal dominant Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.038

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.33

CADD

Benign

2.1

DANN

Benign

0.56

DEOGEN2

Benign

0.24

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0032

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0000042

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.4

MutationTaster

Benign

0.38

PrimateAI

Benign

0.37

PROVEAN

Benign

2.9

REVEL

Benign

0.26

Sift

Benign

1.0

Sift4G

Benign

0.64

Polyphen

0.042

Vest4

0.042

MPC

0.31

ClinPred

0.0010

GERP RS

3.6

Varity_R

0.044

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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