rs80109666

Variant summary

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

The NM_000091.5(COL4A3):​c.805G>A​(p.Glu269Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0118 in 1,613,684 control chromosomes in the GnomAD database, including 734 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 (★★). Synonymous variant affecting the same amino acid position (i.e. E269E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.029 ( 164 hom., cov: 32)
Exomes 𝑓: 0.010 ( 570 hom. )

Consequence

COL4A3
NM_000091.5 missense

Scores

1
17

Clinical Significance

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

Conservation

PhyloP100: -1.33
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=0.0018270016).
BP6
Variant 2-227254151-G-A is Benign according to our data. Variant chr2-227254151-G-A is described in ClinVar as [Benign]. Clinvar id is 255006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227254151-G-A is described in Lovd as [Likely_pathogenic]. Variant chr2-227254151-G-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL4A3NM_000091.5 linkuse as main transcriptc.805G>A p.Glu269Lys missense_variant 14/52 ENST00000396578.8
MFF-DTNR_102371.1 linkuse as main transcriptn.1592+5027C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL4A3ENST00000396578.8 linkuse as main transcriptc.805G>A p.Glu269Lys missense_variant 14/521 NM_000091.5 P1Q01955-1
MFF-DTENST00000439598.6 linkuse as main transcriptn.1592+5027C>T intron_variant, non_coding_transcript_variant 1

Frequencies

GnomAD3 genomes
AF:
0.0293
AC:
4460
AN:
152098
Hom.:
164
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0672
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0153
Gnomad ASJ
AF:
0.00922
Gnomad EAS
AF:
0.143
Gnomad SAS
AF:
0.0253
Gnomad FIN
AF:
0.0271
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.00297
Gnomad OTH
AF:
0.0230
GnomAD3 exomes
AF:
0.0232
AC:
5790
AN:
249418
Hom.:
284
AF XY:
0.0214
AC XY:
2894
AN XY:
135310
show subpopulations
Gnomad AFR exome
AF:
0.0694
Gnomad AMR exome
AF:
0.00727
Gnomad ASJ exome
AF:
0.0142
Gnomad EAS exome
AF:
0.153
Gnomad SAS exome
AF:
0.0160
Gnomad FIN exome
AF:
0.0276
Gnomad NFE exome
AF:
0.00337
Gnomad OTH exome
AF:
0.0182
GnomAD4 exome
AF:
0.00999
AC:
14606
AN:
1461468
Hom.:
570
Cov.:
31
AF XY:
0.00994
AC XY:
7226
AN XY:
727076
show subpopulations
Gnomad4 AFR exome
AF:
0.0711
Gnomad4 AMR exome
AF:
0.00805
Gnomad4 ASJ exome
AF:
0.0158
Gnomad4 EAS exome
AF:
0.145
Gnomad4 SAS exome
AF:
0.0146
Gnomad4 FIN exome
AF:
0.0251
Gnomad4 NFE exome
AF:
0.00165
Gnomad4 OTH exome
AF:
0.0194
GnomAD4 genome
AF:
0.0293
AC:
4465
AN:
152216
Hom.:
164
Cov.:
32
AF XY:
0.0306
AC XY:
2276
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0673
Gnomad4 AMR
AF:
0.0152
Gnomad4 ASJ
AF:
0.00922
Gnomad4 EAS
AF:
0.143
Gnomad4 SAS
AF:
0.0249
Gnomad4 FIN
AF:
0.0271
Gnomad4 NFE
AF:
0.00296
Gnomad4 OTH
AF:
0.0232
Alfa
AF:
0.0113
Hom.:
127
Bravo
AF:
0.0312
TwinsUK
AF:
0.00216
AC:
8
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.0666
AC:
253
ESP6500EA
AF:
0.00243
AC:
20
ExAC
AF:
0.0234
AC:
2822
Asia WGS
AF:
0.0960
AC:
332
AN:
3478
EpiCase
AF:
0.00316
EpiControl
AF:
0.00373

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:5
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 06, 2023- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
not specified Benign:4
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.Glu269Lys in exon 14 of COL4A3: This variant is not expected to have clinical significance because it has been identified in 15.00% (1291/8608) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs80109666). -
Benign, criteria provided, single submitterclinical testingGeneDxOct 05, 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, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpSep 23, 2019Variant summary: COL4A3 c.805G>A (p.Glu269Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.023 in 249418 control chromosomes, predominantly at a frequency of 0.15 within the East Asian subpopulation in the gnomAD database, including 220 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 73-folds over the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing Alport Syndrome, autosomal recessive phenotype (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.805G>A has been reported in the literature in an individual affected with Alport Syndrome, autosomal recessive, however, authors classify the variant as a polymorphism (Zhang_2012). Four ClinVar submissions (evaluation after 2014) cite the variant three times as benign and once as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
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;C5882663:Autosomal dominant Alport syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsJun 01, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Benign
-0.53
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
0.019
DANN
Benign
0.70
DEOGEN2
Benign
0.18
T
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.74
T
MetaRNN
Benign
0.0018
T
MetaSVM
Benign
-0.75
T
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-1.5
N
REVEL
Uncertain
0.33
Sift
Benign
0.92
T
Sift4G
Benign
0.85
T
Polyphen
0.75
P
Vest4
0.081
MPC
0.24
ClinPred
0.0082
T
GERP RS
-5.1
Varity_R
0.048
gMVP
0.43

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.

Other links and lift over

dbSNP: rs80109666; hg19: chr2-228118867; COSMIC: COSV67414559; API