2-227282377-A-G

Position:

chr2-227282377-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000091.5(COL4A3):c.2501A>G(p.Lys834Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,613,086 control chromosomes in the GnomAD database, including 231 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 (★★).

Frequency

Genomes: 𝑓 0.010 ( 12 hom., cov: 31)

Exomes 𝑓: 0.016 ( 219 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.193

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=0.0045960248).

BP6

Variant 2-227282377-A-G is Benign according to our data. Variant chr2-227282377-A-G is described in ClinVar as [Benign]. Clinvar id is 254987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227282377-A-G is described in Lovd as [Likely_benign]. Variant chr2-227282377-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0103 (1563/151726) while in subpopulation NFE AF= 0.0178 (1208/67966). AF 95% confidence interval is 0.0169. There are 12 homozygotes in gnomad4. There are 694 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.2501A>G	p.Lys834Arg	missense_variant	32/52	ENST00000396578.8	NP_000082.2
MFF-DT	NR_102371.1 linkuse as main transcript	n.244-588T>C		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.2501A>G	p.Lys834Arg	missense_variant	32/52	1	NM_000091.5	ENSP00000379823	P1	Q01955-1
MFF-DT	ENST00000439598.6 linkuse as main transcript	n.244-588T>C		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

AF:

0.0103

AC:

1564

AN:

151608

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00368

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00354

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0178

Gnomad OTH

AF:

0.00720

GnomAD3 exomes

AF:

0.0120

AC:

2983

AN:

249468

Hom.:

AF XY:

0.0116

AC XY:

1572

AN XY:

135348

show subpopulations

Gnomad AFR exome

AF:

0.00194

Gnomad AMR exome

AF:

0.00565

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00415

Gnomad FIN exome

AF:

0.0122

Gnomad NFE exome

AF:

0.0194

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0158

AC:

23100

AN:

1461360

Hom.:

219

Cov.:

AF XY:

0.0153

AC XY:

11152

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.00194

Gnomad4 AMR exome

AF:

0.00552

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00436

Gnomad4 FIN exome

AF:

0.0141

Gnomad4 NFE exome

AF:

0.0185

Gnomad4 OTH exome

AF:

0.0124

GnomAD4 genome

AF:

0.0103

AC:

1563

AN:

151726

Hom.:

Cov.:

AF XY:

0.00936

AC XY:

694

AN XY:

74148

show subpopulations

Gnomad4 AFR

AF:

0.00274

Gnomad4 AMR

AF:

0.00368

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00333

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.0178

Gnomad4 OTH

AF:

0.00713

Alfa

AF:

0.0150

Hom.:

Bravo

AF:

0.00950

TwinsUK

AF:

0.0181

AC:

ALSPAC

AF:

0.0145

AC:

ESP6500AA

AF:

0.00220

AC:

ESP6500EA

AF:

0.0147

AC:

120

ExAC

AF:

0.0124

AC:

1498

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0161

EpiControl

AF:

0.0145

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys834Arg in exon 32 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 1.88% (1250/66618) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs56226424). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 02, 2018	This variant is associated with the following publications: (PMID: 19525337, 14582039, 17216251) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Alport syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 27, 2019	- -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 11, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

5.6

DANN

Benign

0.42

DEOGEN2

Benign

0.28

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.048

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.69

MutationAssessor

Benign

-0.050

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.49

REVEL

Benign

0.13

Sift

Benign

0.35

Sift4G

Benign

0.51

Polyphen

0.025

Vest4

0.040

MPC

0.15

ClinPred

0.00072

GERP RS

1.3

Varity_R

0.037

gMVP

0.22

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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