rs200286254
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_002700.3(POU4F3):c.403C>T(p.Pro135Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,608,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P135P) has been classified as Likely benign.
Frequency
Consequence
NM_002700.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POU4F3 | NM_002700.3 | c.403C>T | p.Pro135Ser | missense_variant | 2/2 | ENST00000646991.2 | |
LOC127814297 | NM_001414499.1 | c.*272C>T | 3_prime_UTR_variant | 20/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POU4F3 | ENST00000646991.2 | c.403C>T | p.Pro135Ser | missense_variant | 2/2 | NM_002700.3 | P1 | ||
ENST00000515598.1 | n.404-32554G>A | intron_variant, non_coding_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000203 AC: 5AN: 246206Hom.: 0 AF XY: 0.0000299 AC XY: 4AN XY: 133650
GnomAD4 exome AF: 0.0000275 AC: 40AN: 1456692Hom.: 0 Cov.: 31 AF XY: 0.0000331 AC XY: 24AN XY: 724964
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Autosomal dominant nonsyndromic hearing loss 15 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 15, 2021 | - - |
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Oct 09, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 04, 2014 | Variant classified as Uncertain Significance - Favor Benign. The Pro135Ser varia nt in POU4F3 has not been previously reported in individuals with hearing loss, but has been identified in 0.02% (2/8598) of European American chromosomes by th e NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs200 286254). Computational prediction tools and conservation analyses suggest that t he Pro135Ser variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of this variant cannot be determined with certainty; however based upon the c omputational data and the presence of the variant in the general population, we would lean towards a more likely benign role. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at