2-227270915-C-T

Position:

chr2-227270915-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000091.5(COL4A3):c.1721C>T(p.Pro574Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.479 in 1,613,562 control chromosomes in the GnomAD database, including 189,564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 13008 hom., cov: 31)

Exomes 𝑓: 0.49 ( 176556 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.57

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 -16 ACMG points.

BP6

Variant 2-227270915-C-T is Benign according to our data. Variant chr2-227270915-C-T is described in ClinVar as [Benign]. Clinvar id is 254985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227270915-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.557 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.1721C>T	p.Pro574Leu	missense_variant	25/52	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.1721C>T	p.Pro574Leu	missense_variant	25/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.394

AC:

59799

AN:

151772

Hom.:

13014

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.333

Gnomad AMR

AF:

0.405

Gnomad ASJ

AF:

0.422

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.576

Gnomad FIN

AF:

0.463

Gnomad MID

AF:

0.382

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.391

GnomAD3 exomes

AF:

0.469

AC:

116885

AN:

249312

Hom.:

28472

AF XY:

0.478

AC XY:

64672

AN XY:

135304

show subpopulations

Gnomad AFR exome

AF:

0.182

Gnomad AMR exome

AF:

0.469

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.462

Gnomad SAS exome

AF:

0.586

Gnomad FIN exome

AF:

0.465

Gnomad NFE exome

AF:

0.482

Gnomad OTH exome

AF:

0.458

GnomAD4 exome

AF:

0.488

AC:

713093

AN:

1461670

Hom.:

176556

Cov.:

AF XY:

0.490

AC XY:

356514

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.188

Gnomad4 AMR exome

AF:

0.463

Gnomad4 ASJ exome

AF:

0.436

Gnomad4 EAS exome

AF:

0.481

Gnomad4 SAS exome

AF:

0.586

Gnomad4 FIN exome

AF:

0.469

Gnomad4 NFE exome

AF:

0.495

Gnomad4 OTH exome

AF:

0.461

GnomAD4 genome

AF:

0.394

AC:

59807

AN:

151892

Hom.:

13008

Cov.:

AF XY:

0.395

AC XY:

29273

AN XY:

74198

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.406

Gnomad4 ASJ

AF:

0.422

Gnomad4 EAS

AF:

0.470

Gnomad4 SAS

AF:

0.575

Gnomad4 FIN

AF:

0.463

Gnomad4 NFE

AF:

0.484

Gnomad4 OTH

AF:

0.385

Alfa

AF:

0.464

Hom.:

26829

Bravo

AF:

0.377

TwinsUK

AF:

0.500

AC:

1855

ALSPAC

AF:

0.497

AC:

1914

ESP6500AA

AF:

0.210

AC:

782

ESP6500EA

AF:

0.470

AC:

3848

ExAC

AF:

0.469

AC:

56654

Asia WGS

AF:

0.456

AC:

1586

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:8

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro574Leu in exon 25 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 58.90% (9722/16506) of South Asia n chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs28381984). -
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	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
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	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	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 72% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 67. Only high quality variants are reported. -

not provided

Benign:2

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.	Mar 04, 2021	- -

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

-0.32

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.3

MutationAssessor

Pathogenic

3.3

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.39

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.017

Polyphen

1.0

Vest4

0.14

MPC

0.73

ClinPred

0.024

GERP RS

5.8

Varity_R

0.18

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.23

Position offset: 37

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