rs55816283

Positions:

chr2-227293305-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000091.5(COL4A3):c.3325C>T(p.Pro1109Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00601 in 1,613,784 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0041 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 44 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 1.45

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0191468).

BP6

Variant 2-227293305-C-T is Benign according to our data. Variant chr2-227293305-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 254993.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=4}. Variant chr2-227293305-C-T is described in Lovd as [Likely_benign]. Variant chr2-227293305-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00414 (631/152296) while in subpopulation NFE AF= 0.00609 (414/68028). AF 95% confidence interval is 0.0056. There are 4 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL4A3	NM_000091.5 linkuse as main transcript	c.3325C>T	p.Pro1109Ser	missense_variant	38/52	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.3325C>T	p.Pro1109Ser	missense_variant	38/52	1	NM_000091.5	ENSP00000379823.3		Q01955-1

Frequencies

GnomAD3 genomes

AF:

0.00415

AC:

632

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00320

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00610

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00430

AC:

1072

AN:

249366

Hom.:

AF XY:

0.00458

AC XY:

620

AN XY:

135318

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.00255

Gnomad ASJ exome

AF:

0.0108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00366

Gnomad FIN exome

AF:

0.00278

Gnomad NFE exome

AF:

0.00582

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00621

AC:

9070

AN:

1461488

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

4460

AN XY:

727056

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00320

Gnomad4 ASJ exome

AF:

0.0119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00375

Gnomad4 FIN exome

AF:

0.00262

Gnomad4 NFE exome

AF:

0.00699

Gnomad4 OTH exome

AF:

0.00537

GnomAD4 genome

AF:

0.00414

AC:

631

AN:

152296

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

296

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.0121

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00320

Gnomad4 NFE

AF:

0.00609

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00629

Hom.:

Bravo

AF:

0.00419

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00108

AC:

ESP6500EA

AF:

0.00735

AC:

ExAC

AF:

0.00423

AC:

511

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00567

EpiControl

AF:

0.00699

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely 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	GeneDx	Feb 19, 2019	This variant is associated with the following publications: (PMID: 14871398, 12028435, 17216251, 29981437) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	COL4A3: BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 08, 2022	Variant summary: COL4A3 c.3325C>T (p.Pro1109Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0042 in 280758 control chromosomes with 7 homozygotes (gnomAD), occuring predominantly at a frequency of 0.0057 within the Non-Finnish European subpopulation in the gnomAD database with 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (0.0019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3325C>T has been reported in the literature in individuals affected with Kidney Disorders (Longo_2002, Wang_2004, Papazachariou_2014, Kovacs_2016), often times reported as a polymorphism due to its heterozygosity index (Wang_2004), high mean allele frequency (Papazachariou_2014), or other variants being causitive of disease (Kovacs_2016). These reports suggest the variant is not likely to be associated with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, one as likely benign, and three as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Pro1109Ser in exon 38 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 0.56% (376/66566) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs55816283). -

Alport syndrome

Uncertain:1

Uncertain significance, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Kidney disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2019

- -

COL4A3-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

D;.

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.93

D;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.019

T;T

MetaSVM

Pathogenic

0.86

MutationAssessor

Benign

1.5

L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.0

N;D

REVEL

Uncertain

0.52

Sift

Uncertain

0.0070

D;D

Sift4G

Benign

0.13

T;T

Polyphen

0.75

P;.

Vest4

0.50

MVP

0.87

MPC

0.19

ClinPred

0.012

GERP RS

4.8

Varity_R

0.14

gMVP

0.36

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