chrX-83508463-C-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_000307.5(POU3F4):c.139C>T(p.Pro47Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00027 in 1,208,648 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 102 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000307.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
POU3F4 | NM_000307.5 | c.139C>T | p.Pro47Ser | missense_variant | Exon 1 of 1 | ENST00000644024.2 | NP_000298.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
POU3F4 | ENST00000644024.2 | c.139C>T | p.Pro47Ser | missense_variant | Exon 1 of 1 | NM_000307.5 | ENSP00000495996.1 | |||
ENSG00000279437 | ENST00000625081.1 | n.752G>A | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 |
Frequencies
GnomAD3 genomes AF: 0.00107 AC: 120AN: 112590Hom.: 0 Cov.: 23 AF XY: 0.000749 AC XY: 26AN XY: 34734
GnomAD3 exomes AF: 0.000408 AC: 72AN: 176341Hom.: 0 AF XY: 0.000277 AC XY: 17AN XY: 61441
GnomAD4 exome AF: 0.000188 AC: 206AN: 1096008Hom.: 0 Cov.: 31 AF XY: 0.000210 AC XY: 76AN XY: 361540
GnomAD4 genome AF: 0.00107 AC: 120AN: 112640Hom.: 0 Cov.: 23 AF XY: 0.000747 AC XY: 26AN XY: 34794
ClinVar
Submissions by phenotype
not provided Benign:3
The POU3F4 p.Pro47Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs144417952) and ClinVar (classified as likely benign by Laboratory for Molecular Medicine and Illumina). The variant was also identified in control databases in 97 of 198285 chromosomes (26 hemizygous) at a frequency of 0.000489 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 76 of 18537 chromosomes (freq: 0.0041), Latino in 7 of 27514 chromosomes (freq: 0.000254) and European (non-Finnish) in 14 of 88908 chromosomes (freq: 0.000158), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Pro47 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
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POU3F4-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not specified Benign:1
p.Pro47Ser in Exon 1 of POU3F4: This variant is not expected to have clinical si gnificance because it has been identified in 0.4% (14/3216) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS; dbSNP rs144417952). -
X-linked mixed hearing loss with perilymphatic gusher Benign:1
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at