chr2-227238007-G-C

Variant summary

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

The NM_000091.5(COL4A3):​c.127G>C​(p.Gly43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,604,472 control chromosomes in the GnomAD database, including 97,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 8201 hom., cov: 31)
Exomes 𝑓: 0.34 ( 89577 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

1
10
7

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 1.14
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]
MFF-DT (HGNC:41067): (MFF divergent transcript)

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=0.005469084).
BP6
Variant 2-227238007-G-C is Benign according to our data. Variant chr2-227238007-G-C is described in ClinVar as [Benign]. Clinvar id is 254978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227238007-G-C is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A3NM_000091.5 linkuse as main transcriptc.127G>C p.Gly43Arg missense_variant 2/52 ENST00000396578.8 NP_000082.2
MFF-DTNR_102371.1 linkuse as main transcriptn.1681+79C>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A3ENST00000396578.8 linkuse as main transcriptc.127G>C p.Gly43Arg missense_variant 2/521 NM_000091.5 ENSP00000379823 P1Q01955-1
MFF-DTENST00000439598.6 linkuse as main transcriptn.1681+79C>G intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.319
AC:
48484
AN:
151848
Hom.:
8194
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.313
Gnomad AMI
AF:
0.549
Gnomad AMR
AF:
0.274
Gnomad ASJ
AF:
0.349
Gnomad EAS
AF:
0.0488
Gnomad SAS
AF:
0.140
Gnomad FIN
AF:
0.339
Gnomad MID
AF:
0.274
Gnomad NFE
AF:
0.359
Gnomad OTH
AF:
0.323
GnomAD3 exomes
AF:
0.284
AC:
70806
AN:
249520
Hom.:
11647
AF XY:
0.282
AC XY:
38196
AN XY:
135370
show subpopulations
Gnomad AFR exome
AF:
0.308
Gnomad AMR exome
AF:
0.218
Gnomad ASJ exome
AF:
0.337
Gnomad EAS exome
AF:
0.0388
Gnomad SAS exome
AF:
0.140
Gnomad FIN exome
AF:
0.334
Gnomad NFE exome
AF:
0.362
Gnomad OTH exome
AF:
0.314
GnomAD4 exome
AF:
0.341
AC:
494969
AN:
1452506
Hom.:
89577
Cov.:
28
AF XY:
0.334
AC XY:
241510
AN XY:
723070
show subpopulations
Gnomad4 AFR exome
AF:
0.311
Gnomad4 AMR exome
AF:
0.226
Gnomad4 ASJ exome
AF:
0.345
Gnomad4 EAS exome
AF:
0.0735
Gnomad4 SAS exome
AF:
0.144
Gnomad4 FIN exome
AF:
0.331
Gnomad4 NFE exome
AF:
0.373
Gnomad4 OTH exome
AF:
0.322
GnomAD4 genome
AF:
0.319
AC:
48521
AN:
151966
Hom.:
8201
Cov.:
31
AF XY:
0.309
AC XY:
22974
AN XY:
74262
show subpopulations
Gnomad4 AFR
AF:
0.313
Gnomad4 AMR
AF:
0.273
Gnomad4 ASJ
AF:
0.349
Gnomad4 EAS
AF:
0.0487
Gnomad4 SAS
AF:
0.140
Gnomad4 FIN
AF:
0.339
Gnomad4 NFE
AF:
0.359
Gnomad4 OTH
AF:
0.319
Alfa
AF:
0.322
Hom.:
5112
Bravo
AF:
0.318
TwinsUK
AF:
0.396
AC:
1469
ALSPAC
AF:
0.378
AC:
1457
ESP6500AA
AF:
0.306
AC:
1134
ESP6500EA
AF:
0.371
AC:
3032
ExAC
AF:
0.288
AC:
34832
Asia WGS
AF:
0.123
AC:
427
AN:
3478
EpiCase
AF:
0.357
EpiControl
AF:
0.363

ClinVar

Significance: Benign
Submissions summary: Benign:15
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 21, 2016p.Gly43Arg in exon 2 of COL4A3: This variant is not expected to have clinical si gnificance because it has been identified in 36.20% (24153/66730) of European ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs13424243). -
Benign, criteria provided, single submitterclinical testingGeneDxMay 09, 2017This 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, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJul 15, 2024This variant is classified as Benign based on local population frequency. This variant was detected in 31% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 29. Only high quality variants are reported. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 11, 2017Variant summary: The COL4A3 c.127G>C (p.Gly43Arg) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 34826/120756 control chromosomes (5825 homozygotes) at a frequency of 0.2883997, which is approximately 141 times the estimated maximal expected allele frequency of a pathogenic COL4A3 variant (0.0020412), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases/literature classified this variant as benign. Taken together, this variant is classified as benign. -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 29, 2023- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Alport syndrome Benign:2
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
Autosomal recessive Alport syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJun 10, 2021- -
Autosomal recessive Alport syndrome;C5882663:Autosomal dominant Alport syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 28, 2017- -
Autosomal dominant Alport syndrome Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 30, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.51
D
Eigen
Uncertain
0.23
Eigen_PC
Benign
-0.025
FATHMM_MKL
Benign
0.21
N
LIST_S2
Uncertain
0.88
D
MetaRNN
Benign
0.0055
T
MetaSVM
Benign
-1.8
T
MutationAssessor
Pathogenic
4.1
H
MutationTaster
Benign
1.0
P
PrimateAI
Uncertain
0.49
T
PROVEAN
Uncertain
-4.1
D
REVEL
Uncertain
0.41
Sift
Uncertain
0.013
D
Sift4G
Uncertain
0.0050
D
Polyphen
1.0
D
Vest4
0.10
MutPred
0.86
Gain of sheet (P = 0.0344);
MPC
0.82
ClinPred
0.048
T
GERP RS
4.3
Varity_R
0.61
gMVP
0.61

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.

Other links and lift over

dbSNP: rs13424243; hg19: chr2-228102723; COSMIC: COSV67415437; COSMIC: COSV67415437; API