chr15-23565989-A-AGGAGGCC

Position:

• chr15-23565989-A-AGGAGGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_005664.4(MKRN3):​c.208_214dupGGAGGCC​(p.Leu72fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKRN3 NM_005664.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0710

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]

ENSG00000260978 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 7 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-23565989-A-AGGAGGCC is Pathogenic according to our data. Variant chr15-23565989-A-AGGAGGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 817441.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MKRN3	NM_005664.4	c.208_214dupGGAGGCC	p.Leu72fs	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.208_214dupGGAGGCC	p.Leu72fs	frameshift_variant	1/1	6	NM_005664.4	ENSP00000313881.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2019

The c.208_214dupGGAGGCC variant in the MKRN3 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.208_214dupGGAGGCC variant causes a frameshift starting with codon Leucine 72, changes this amino acid to an Arginine residue, and creates a premature Stop codon at position 60 of the new reading frame, denoted p.Leu72ArgfsX60. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 436 amino acids are lost and replaced with 59 incorrect amino acids. The c.208_214dupGGAGGCC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.208_214dupGGAGGCC as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1595298328; hg19: chr15-23811136;