2-227256385-G-T

Position:

chr2-227256385-G-T

Variant summary

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

The NM_000091.5(COL4A3):c.976G>T(p.Asp326Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.191 in 1,610,916 control chromosomes in the GnomAD database, including 31,711 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 0.15 ( 2278 hom., cov: 32)

Exomes 𝑓: 0.19 ( 29433 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.554

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:):

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=0.006026387).

BP6

Variant 2-227256385-G-T is Benign according to our data. Variant chr2-227256385-G-T is described in ClinVar as [Benign]. Clinvar id is 255010.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227256385-G-T is described in Lovd as [Benign]. Variant chr2-227256385-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.213 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.976G>T	p.Asp326Tyr	missense_variant	17/52	ENST00000396578.8	NP_000082.2	Q01955-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL4A3	ENST00000396578.8 linkuse as main transcript	c.976G>T	p.Asp326Tyr	missense_variant	17/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23466

AN:

152034

Hom.:

2280

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0400

Gnomad AMI

AF:

0.356

Gnomad AMR

AF:

0.155

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.118

Gnomad SAS

AF:

0.116

Gnomad FIN

AF:

0.189

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.216

Gnomad OTH

AF:

0.188

GnomAD3 exomes

AF:

0.169

AC:

42103

AN:

249230

Hom.:

4187

AF XY:

0.172

AC XY:

23268

AN XY:

135208

show subpopulations

Gnomad AFR exome

AF:

0.0359

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.231

Gnomad EAS exome

AF:

0.115

Gnomad SAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.192

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.188

GnomAD4 exome

AF:

0.195

AC:

284458

AN:

1458764

Hom.:

29433

Cov.:

AF XY:

0.194

AC XY:

141088

AN XY:

725836

show subpopulations

Gnomad4 AFR exome

AF:

0.0328

Gnomad4 AMR exome

AF:

0.110

Gnomad4 ASJ exome

AF:

0.224

Gnomad4 EAS exome

AF:

0.124

Gnomad4 SAS exome

AF:

0.116

Gnomad4 FIN exome

AF:

0.195

Gnomad4 NFE exome

AF:

0.212

Gnomad4 OTH exome

AF:

0.184

GnomAD4 genome

AF:

0.154

AC:

23463

AN:

152152

Hom.:

2278

Cov.:

AF XY:

0.152

AC XY:

11315

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.0398

Gnomad4 AMR

AF:

0.155

Gnomad4 ASJ

AF:

0.234

Gnomad4 EAS

AF:

0.118

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.189

Gnomad4 NFE

AF:

0.216

Gnomad4 OTH

AF:

0.188

Alfa

AF:

0.204

Hom.:

4781

Bravo

AF:

0.148

TwinsUK

AF:

0.206

AC:

764

ALSPAC

AF:

0.208

AC:

802

ESP6500AA

AF:

0.0429

AC:

159

ESP6500EA

AF:

0.221

AC:

1814

ExAC

AF:

0.167

AC:

20129

Asia WGS

AF:

0.129

AC:

449

AN:

3478

EpiCase

AF:

0.235

EpiControl

AF:

0.230

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Asp326Tyr in exon 17 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 21.64% (14422/66634) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs55703767). -
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	Athena Diagnostics	Apr 22, 2021	- -
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 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

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 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. -

not provided

Benign:2

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	- -

Autosomal recessive Alport syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Uncertain

0.61

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.9

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.19

Sift

Benign

0.11

Sift4G

Benign

0.067

Polyphen

0.29

Vest4

0.092

MPC

0.66

ClinPred

0.013

GERP RS

3.0

Varity_R

0.20

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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