15-23566257-GC-GCC
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PVS1_StrongPP5BS2
The NM_005664.4(MKRN3):c.482dup(p.Ala162GlyfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,613,582 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )
Consequence
MKRN3
NM_005664.4 frameshift
NM_005664.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.492
Genes affected
MKRN3 (HGNC:7114): (makorin ring finger protein 3) The protein encoded by this gene contains a RING (C3HC4) zinc finger motif and several C3H zinc finger motifs. This gene is intronless and imprinted, with expression only from the paternal allele. Disruption of the imprinting at this locus may contribute to Prader-Willi syndrome. An antisense RNA of unknown function has been found overlapping this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PP5
Variant 15-23566257-G-GC is Pathogenic according to our data. Variant chr15-23566257-G-GC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 56904.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 7 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MKRN3 | NM_005664.4 | c.482dup | p.Ala162GlyfsTer15 | frameshift_variant | 1/1 | ENST00000314520.6 | NP_005655.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MKRN3 | ENST00000314520.6 | c.482dup | p.Ala162GlyfsTer15 | frameshift_variant | 1/1 | NM_005664.4 | ENSP00000313881 | P1 | ||
ENST00000563044.2 | n.1572_1573insG | non_coding_transcript_exon_variant | 2/2 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.0000404 AC: 59AN: 1461390Hom.: 0 Cov.: 30 AF XY: 0.0000358 AC XY: 26AN XY: 726996
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74348
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
MKRN3-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 24, 2023 | The MKRN3 c.482dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala162Glyfs*15). This variant has been reported to be causative for central precocious puberty (Abreu et al. 2013. PubMed ID: 23738509; Macedo et al. 2014. PubMed ID: 24628548; Schreiner et al. 2014. PubMed ID: 25011910; Simon et al. 2016. PubMed ID: 26431553; Bessa et al. 2017. PubMed ID: 27225315). Please note that MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region and all affected individuals inherited the pathogenic variants from their fathers. This variant is reported in 0.013% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/15-23811404-G-GC). Frameshift variants in MKRN3 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Precocious puberty, central, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 27, 2013 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 05, 2022 | Frameshift variant predicted to result in protein truncation, as the last 346 amino acids are replaced with 14 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Also known as c.475_476insC and c.482_483insC; This variant is associated with the following publications: (PMID: 30675365, 24628548, 26431553, 31589614, 33383582, 32676665, 23738509, 25011910) - |
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at