chr5-146340375-C-G
Variant names:
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1BP4BP6BS1BS2
The NM_002700.3(POU4F3):āc.948C>Gā(p.Asn316Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,614,204 control chromosomes in the GnomAD database, including 1 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: š 0.00051 ( 0 hom., cov: 33)
Exomes š: 0.00087 ( 1 hom. )
Consequence
POU4F3
NM_002700.3 missense
NM_002700.3 missense
Scores
5
9
5
Clinical Significance
Conservation
PhyloP100: 2.26
Genes affected
POU4F3 (HGNC:9220): (POU class 4 homeobox 3) This gene encodes a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important roles in control of cell identity in several systems. This protein is found in the retina and may play a role in determining or maintaining the identities of a small subset of visual system neurons. Defects in this gene are the cause of non-syndromic sensorineural deafness autosomal dominant type 15. [provided by RefSeq, Mar 2009]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
PM1
In a DNA_binding_region Homeobox (size 59) in uniprot entity PO4F3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002700.3
BP4
Computational evidence support a benign effect (MetaRNN=0.3540775).
BP6
Variant 5-146340375-C-G is Benign according to our data. Variant chr5-146340375-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351386.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000512 (78/152312) while in subpopulation NFE AF= 0.000808 (55/68030). AF 95% confidence interval is 0.000638. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 78 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000513 AC: 78AN: 152194Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000390 AC: 98AN: 251330Hom.: 0 AF XY: 0.000375 AC XY: 51AN XY: 135898
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GnomAD4 exome AF: 0.000874 AC: 1278AN: 1461892Hom.: 1 Cov.: 31 AF XY: 0.000770 AC XY: 560AN XY: 727248
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GnomAD4 genome AF: 0.000512 AC: 78AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37AN XY: 74476
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 17, 2024 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 316 of the POU4F3 protein (p.Asn316Lys). This variant is present in population databases (rs149303333, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POU4F3-related conditions. ClinVar contains an entry for this variant (Variation ID: 351386). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POU4F3 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | POU4F3: PP3, BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 15, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 28, 2018 | The p.Asn316Lys variant in POU4F3 has not been previously reported in individual s with hearing loss, but is listed in ClinVar (Variation ID:351386), and has bee n identified in 0.06% (77/126594) of European chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs149303333). Alt hough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and c onservation analyses suggest that this variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asn316Lys variant is uncertain. ACMG/AMP Crit eria applied: PP3. - |
POU4F3-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 28, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Autosomal dominant nonsyndromic hearing loss 15 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;N
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
.;D
REVEL
Uncertain
Sift
Uncertain
.;D
Sift4G
Uncertain
.;D
Polyphen
D;D
Vest4
0.74
MutPred
Gain of methylation at N316 (P = 0.0331);Gain of methylation at N316 (P = 0.0331);
MVP
0.90
MPC
1.4
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at