rs75398746
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_024921.4(POF1B):c.986G>A(p.Arg329Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,178,639 control chromosomes in the GnomAD database, including 5 homozygotes. There are 843 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024921.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POF1B | NM_024921.4 | c.986G>A | p.Arg329Gln | missense_variant | 10/17 | ENST00000262753.9 | |
POF1B | NM_001307940.2 | c.986G>A | p.Arg329Gln | missense_variant | 10/16 | ||
POF1B | XM_005262203.5 | c.941G>A | p.Arg314Gln | missense_variant | 10/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POF1B | ENST00000262753.9 | c.986G>A | p.Arg329Gln | missense_variant | 10/17 | 1 | NM_024921.4 | A2 | |
POF1B | ENST00000373145.3 | c.986G>A | p.Arg329Gln | missense_variant | 10/16 | 1 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00350 AC: 390AN: 111400Hom.: 1 Cov.: 23 AF XY: 0.00327 AC XY: 110AN XY: 33634
GnomAD3 exomes AF: 0.00271 AC: 461AN: 170226Hom.: 0 AF XY: 0.00223 AC XY: 127AN XY: 56824
GnomAD4 exome AF: 0.00217 AC: 2320AN: 1067190Hom.: 4 Cov.: 25 AF XY: 0.00216 AC XY: 733AN XY: 339504
GnomAD4 genome ? AF: 0.00350 AC: 390AN: 111449Hom.: 1 Cov.: 23 AF XY: 0.00326 AC XY: 110AN XY: 33693
ClinVar
Submissions by phenotype
Premature ovarian failure 2B Pathogenic:3Uncertain:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2006 | - - |
Likely pathogenic, no assertion criteria provided | research | Reproductive Development, Murdoch Childrens Research Institute | Feb 09, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Uncertain significance. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 26, 2018 | Lacombe et al. (2006) identified the POF1B c.986G>A (p.Arg329Gln) variant in a homozygous state in five sisters with POF from a consanguineous Lebanese family. The variant was also identified in a heterozygous state in the unaffected mother and an unaffected sister. The p.Arg329Gln variant has also been reported in two additional patients with POF, including in a heterozygous state in one patient with a second unidentified variant and in one patient with the p.Arg329Gln variant on one allele and a balanced translocation on the other (Bione et al. 2004; Ledig et al. 2015). The p.Arg329Gln variant was found in a heterozygous state in a total of seven of 992 controls from the above studies, and is reported at a frequency of 0.007634 in the admixed American population of the 1000 Genomes Project. Lacombe et al. (2006) found that in vitro binding to non-muscle actin filaments was diminished four-fold in the p.Arg329Gln variant protein compared to the wild type, and Padovano et al. (2011) demonstrated that cells expressing the p.Arg329Gln variant have mislocalized and misassembled tight junctions, were dysmorphic with altered monolayer organization, and showed defects in ciliogenesis and cystogenesis. Based on the evidence, the p.Arg329Gln variant is classified as as a variant of unknown significance but suspicious for pathogenicity for premature ovarian failure 2B. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 19, 2020 | - - |
Premature ovarian insufficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jun 15, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at