rs34505188

Positions:

Variant summary

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

The NM_000091.5(COL4A3):c.1223G>A(p.Arg408His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,613,942 control chromosomes in the GnomAD database, including 5,700 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 0.073 ( 544 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5156 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.914

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=0.0022709966).

BP6

Variant 2-227263852-G-A is Benign according to our data. Variant chr2-227263852-G-A is described in ClinVar as [Benign]. Clinvar id is 254977.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227263852-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.157 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.1223G>A	p.Arg408His	missense_variant	21/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1 linkuse as main transcript	n.1486+817C>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.1223G>A	p.Arg408His	missense_variant	21/52	1	NM_000091.5	ENSP00000379823	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.1486+817C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0725

AC:

11038

AN:

152156

Hom.:

537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0329

Gnomad AMI

AF:

0.0592

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.105

Gnomad FIN

AF:

0.0315

Gnomad MID

AF:

0.0981

Gnomad NFE

AF:

0.0729

Gnomad OTH

AF:

0.0829

GnomAD3 exomes

AF:

0.0943

AC:

23514

AN:

249242

Hom.:

1396

AF XY:

0.0938

AC XY:

12690

AN XY:

135254

show subpopulations

Gnomad AFR exome

AF:

0.0330

Gnomad AMR exome

AF:

0.176

Gnomad ASJ exome

AF:

0.0899

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0311

Gnomad NFE exome

AF:

0.0760

Gnomad OTH exome

AF:

0.0999

GnomAD4 exome

AF:

0.0789

AC:

115270

AN:

1461668

Hom.:

5156

Cov.:

AF XY:

0.0798

AC XY:

58023

AN XY:

727142

show subpopulations

Gnomad4 AFR exome

AF:

0.0311

Gnomad4 AMR exome

AF:

0.175

Gnomad4 ASJ exome

AF:

0.0902

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0357

Gnomad4 NFE exome

AF:

0.0735

Gnomad4 OTH exome

AF:

0.0893

GnomAD4 genome

AF:

0.0727

AC:

11065

AN:

152274

Hom.:

544

Cov.:

AF XY:

0.0734

AC XY:

5467

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0329

Gnomad4 AMR

AF:

0.163

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.0315

Gnomad4 NFE

AF:

0.0729

Gnomad4 OTH

AF:

0.0896

Alfa

AF:

0.0724

Hom.:

430

Bravo

AF:

0.0809

TwinsUK

AF:

0.0774

AC:

287

ALSPAC

AF:

0.0719

AC:

277

ESP6500AA

AF:

0.0330

AC:

123

ESP6500EA

AF:

0.0770

AC:

630

ExAC

AF:

0.0908

AC:

10968

Asia WGS

AF:

0.138

AC:

481

AN:

3478

EpiCase

AF:

0.0874

EpiControl

AF:

0.0900

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg408His in exon 21 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 17.54% (2026/11552) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs34505188). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 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	PreventionGenetics, part of Exact Sciences	-	- -
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 28% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 26. Only high quality variants are reported. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Alport syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.26

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.26

MetaRNN

Benign

0.0023

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.95

MutationTaster

Benign

1.0

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.34

REVEL

Benign

0.24

Sift

Benign

0.56

Sift4G

Benign

0.13

Polyphen

1.0

Vest4

0.033

MPC

0.79

ClinPred

0.019

GERP RS

2.1

Varity_R

0.031

gMVP

0.14

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