rs34019152

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000091.5(COL4A3):c.1452G>A(p.Gly484=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,612,894 control chromosomes in the GnomAD database, including 5,796 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.078 ( 580 hom., cov: 32)

Exomes 𝑓: 0.079 ( 5216 hom. )

Consequence

COL4A3
NM_000091.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.356

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 2-227267036-G-A is Benign according to our data. Variant chr2-227267036-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 254982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227267036-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.356 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.161 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.1452G>A	p.Gly484=	synonymous_variant	23/52	ENST00000396578.8
MFF-DT	NR_102371.1 linkuse as main transcript	n.656-1101C>T		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.1452G>A	p.Gly484=	synonymous_variant	23/52	1	NM_000091.5	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.656-1101C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0778

AC:

11820

AN:

152014

Hom.:

573

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0494

Gnomad AMI

AF:

0.0581

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.152

Gnomad SAS

AF:

0.106

Gnomad FIN

AF:

0.0313

Gnomad MID

AF:

0.105

Gnomad NFE

AF:

0.0734

Gnomad OTH

AF:

0.0894

GnomAD3 exomes

AF:

0.0957

AC:

23868

AN:

249488

Hom.:

1416

AF XY:

0.0949

AC XY:

12841

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.0503

Gnomad AMR exome

AF:

0.177

Gnomad ASJ exome

AF:

0.0900

Gnomad EAS exome

AF:

0.153

Gnomad SAS exome

AF:

0.111

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0761

Gnomad OTH exome

AF:

0.101

GnomAD4 exome

AF:

0.0793

AC:

115787

AN:

1460760

Hom.:

5216

Cov.:

AF XY:

0.0801

AC XY:

58230

AN XY:

726702

show subpopulations

Gnomad4 AFR exome

AF:

0.0475

Gnomad4 AMR exome

AF:

0.176

Gnomad4 ASJ exome

AF:

0.0900

Gnomad4 EAS exome

AF:

0.122

Gnomad4 SAS exome

AF:

0.112

Gnomad4 FIN exome

AF:

0.0357

Gnomad4 NFE exome

AF:

0.0734

Gnomad4 OTH exome

AF:

0.0909

GnomAD4 genome

AF:

0.0779

AC:

11849

AN:

152134

Hom.:

580

Cov.:

AF XY:

0.0787

AC XY:

5856

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0494

Gnomad4 AMR

AF:

0.167

Gnomad4 ASJ

AF:

0.100

Gnomad4 EAS

AF:

0.152

Gnomad4 SAS

AF:

0.106

Gnomad4 FIN

AF:

0.0313

Gnomad4 NFE

AF:

0.0734

Gnomad4 OTH

AF:

0.0960

Alfa

AF:

0.0746

Hom.:

244

Bravo

AF:

0.0875

Asia WGS

AF:

0.139

AC:

483

AN:

3478

EpiCase

AF:

0.0875

EpiControl

AF:

0.0901

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Gly484Gly in exon 23 of COL4A3: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 17.66% (2037/11532 ) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs34019152). -
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. -

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

May 24, 2017

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Benign familial hematuria;C4746745:Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.94

DANN

Benign

0.48

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