rs57611801

Positions:

Variant summary

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

The ENST00000396578.8(COL4A3):c.3807C>A(p.Asp1269Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,962 control chromosomes in the GnomAD database, including 1,671 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 Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1269D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.057 ( 339 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1332 hom. )

Consequence

COL4A3
ENST00000396578.8 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.256

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020103753).

BP6

Variant 2-227298737-C-A is Benign according to our data. Variant chr2-227298737-C-A is described in ClinVar as [Benign]. Clinvar id is 254995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227298737-C-A is described in Lovd as [Benign]. Variant chr2-227298737-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0951 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.3807C>A	p.Asp1269Glu	missense_variant	43/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1 linkuse as main transcript	n.243+6723G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.3807C>A	p.Asp1269Glu	missense_variant	43/52	1	NM_000091.5	ENSP00000379823	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.243+6723G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0574

AC:

8726

AN:

152102

Hom.:

340

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0978

Gnomad AMI

AF:

0.0417

Gnomad AMR

AF:

0.0523

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0165

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0359

Gnomad OTH

AF:

0.0474

GnomAD3 exomes

AF:

0.0449

AC:

11209

AN:

249456

Hom.:

395

AF XY:

0.0417

AC XY:

5645

AN XY:

135354

show subpopulations

Gnomad AFR exome

AF:

0.0982

Gnomad AMR exome

AF:

0.0760

Gnomad ASJ exome

AF:

0.0214

Gnomad EAS exome

AF:

0.00250

Gnomad SAS exome

AF:

0.0177

Gnomad FIN exome

AF:

0.0974

Gnomad NFE exome

AF:

0.0348

Gnomad OTH exome

AF:

0.0363

GnomAD4 exome

AF:

0.0370

AC:

54112

AN:

1461742

Hom.:

1332

Cov.:

AF XY:

0.0361

AC XY:

26219

AN XY:

727164

show subpopulations

Gnomad4 AFR exome

AF:

0.0959

Gnomad4 AMR exome

AF:

0.0732

Gnomad4 ASJ exome

AF:

0.0194

Gnomad4 EAS exome

AF:

0.00141

Gnomad4 SAS exome

AF:

0.0184

Gnomad4 FIN exome

AF:

0.0916

Gnomad4 NFE exome

AF:

0.0344

Gnomad4 OTH exome

AF:

0.0372

GnomAD4 genome

AF:

0.0574

AC:

8731

AN:

152220

Hom.:

339

Cov.:

AF XY:

0.0599

AC XY:

4462

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0976

Gnomad4 AMR

AF:

0.0523

Gnomad4 ASJ

AF:

0.0202

Gnomad4 EAS

AF:

0.00231

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.0359

Gnomad4 OTH

AF:

0.0469

Alfa

AF:

0.0376

Hom.:

126

Bravo

AF:

0.0558

TwinsUK

AF:

0.0248

AC:

ALSPAC

AF:

0.0371

AC:

143

ESP6500AA

AF:

0.0975

AC:

365

ESP6500EA

AF:

0.0282

AC:

232

ExAC

AF:

0.0440

AC:

5313

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.0316

EpiControl

AF:

0.0314

ClinVar

Significance: Benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asp1269Glu in exon 43 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 10.45% (691/6614) of Finnish chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs57611801). -
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. -

not provided

Benign:5

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 22, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Alport syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
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. -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Atypical hemolytic-uremic syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.33

CADD

Benign

9.8

DANN

Benign

0.68

DEOGEN2

Benign

0.063

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0020

MetaSVM

Benign

-0.67

MutationAssessor

Benign

0.21

MutationTaster

Benign

0.70

PrimateAI

Benign

0.41

PROVEAN

Benign

0.53

REVEL

Benign

0.27

Sift

Benign

0.38

Sift4G

Benign

0.96

Polyphen

0.022

Vest4

0.042

MutPred

0.11

Loss of MoRF binding (P = 0.2243);

MPC

0.18

ClinPred

0.0016

GERP RS

0.78

Varity_R

0.046

gMVP

0.11

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