rs2229814

Variant summary

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

The NM_000092.5(COL4A4):​c.1444C>T​(p.Pro482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.511 in 1,610,152 control chromosomes in the GnomAD database, including 212,777 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 0.51 ( 20000 hom., cov: 29)
Exomes 𝑓: 0.51 ( 192777 hom. )

Consequence

COL4A4
NM_000092.5 missense

Scores

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.668
Variant links:
Genes affected
COL4A4 (HGNC:2206): (collagen type IV alpha 4 chain) This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

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=6.3470297E-6).
BP6
Variant 2-227089883-G-A is Benign according to our data. Variant chr2-227089883-G-A is described in ClinVar as [Benign]. Clinvar id is 255014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227089883-G-A is described in Lovd as [Benign]. Variant chr2-227089883-G-A is described in Lovd as [Likely_benign].
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL4A4NM_000092.5 linkuse as main transcriptc.1444C>T p.Pro482Ser missense_variant 21/48 ENST00000396625.5 NP_000083.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL4A4ENST00000396625.5 linkuse as main transcriptc.1444C>T p.Pro482Ser missense_variant 21/485 NM_000092.5 ENSP00000379866 P1

Frequencies

GnomAD3 genomes
AF:
0.513
AC:
77589
AN:
151114
Hom.:
19978
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.504
Gnomad AMI
AF:
0.498
Gnomad AMR
AF:
0.582
Gnomad ASJ
AF:
0.528
Gnomad EAS
AF:
0.498
Gnomad SAS
AF:
0.624
Gnomad FIN
AF:
0.522
Gnomad MID
AF:
0.525
Gnomad NFE
AF:
0.496
Gnomad OTH
AF:
0.501
GnomAD3 exomes
AF:
0.540
AC:
134535
AN:
249218
Hom.:
37133
AF XY:
0.538
AC XY:
72729
AN XY:
135214
show subpopulations
Gnomad AFR exome
AF:
0.508
Gnomad AMR exome
AF:
0.666
Gnomad ASJ exome
AF:
0.548
Gnomad EAS exome
AF:
0.487
Gnomad SAS exome
AF:
0.631
Gnomad FIN exome
AF:
0.530
Gnomad NFE exome
AF:
0.491
Gnomad OTH exome
AF:
0.521
GnomAD4 exome
AF:
0.511
AC:
745448
AN:
1458914
Hom.:
192777
Cov.:
37
AF XY:
0.513
AC XY:
372545
AN XY:
725928
show subpopulations
Gnomad4 AFR exome
AF:
0.506
Gnomad4 AMR exome
AF:
0.656
Gnomad4 ASJ exome
AF:
0.553
Gnomad4 EAS exome
AF:
0.507
Gnomad4 SAS exome
AF:
0.630
Gnomad4 FIN exome
AF:
0.531
Gnomad4 NFE exome
AF:
0.494
Gnomad4 OTH exome
AF:
0.509
GnomAD4 genome
AF:
0.514
AC:
77667
AN:
151238
Hom.:
20000
Cov.:
29
AF XY:
0.516
AC XY:
38123
AN XY:
73820
show subpopulations
Gnomad4 AFR
AF:
0.504
Gnomad4 AMR
AF:
0.582
Gnomad4 ASJ
AF:
0.528
Gnomad4 EAS
AF:
0.498
Gnomad4 SAS
AF:
0.624
Gnomad4 FIN
AF:
0.522
Gnomad4 NFE
AF:
0.496
Gnomad4 OTH
AF:
0.502
Alfa
AF:
0.501
Hom.:
30521
Bravo
AF:
0.517
TwinsUK
AF:
0.498
AC:
1845
ALSPAC
AF:
0.481
AC:
1853
ESP6500AA
AF:
0.525
AC:
1967
ESP6500EA
AF:
0.502
AC:
4115
ExAC
AF:
0.534
AC:
64523
EpiCase
AF:
0.476
EpiControl
AF:
0.486

ClinVar

Significance: Benign
Submissions summary: Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
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 73% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 68. Only high quality variants are reported. -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 21, 2016p.Pro482Ser in exon 21 of COL4A4: This variant is not expected to have clinical significance because it has been identified in 68.08% (7860/11546) of Latino chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs2229814). -
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 testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
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 LabJul 10, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.48
CADD
Benign
11
DANN
Benign
0.34
DEOGEN2
Benign
0.072
T
Eigen
Benign
-0.76
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.011
N
LIST_S2
Benign
0.11
T
MetaRNN
Benign
0.0000063
T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.1
L
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.030
N
REVEL
Benign
0.25
Sift
Benign
0.75
T
Sift4G
Benign
0.74
T
Polyphen
0.0
B
Vest4
0.019
MPC
0.14
ClinPred
0.000018
T
GERP RS
0.34
Varity_R
0.028
gMVP
0.047

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs2229814; hg19: chr2-227954599; COSMIC: COSV61630186; API