15-23565885-T-G

Position:

• chr15-23565885-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005664.4(MKRN3):​c.103T>G​(p.Cys35Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKRN3 NM_005664.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.578

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057364702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKRN3	NM_005664.4	c.103T>G	p.Cys35Gly	missense_variant	1/1	ENST00000314520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKRN3	ENST00000314520.6	c.103T>G	p.Cys35Gly	missense_variant	1/1		NM_005664.4	P1
	ENST00000563044.2	n.1945A>C		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Precocious puberty, central, 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Apr 19, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.3
DANN	Benign	0.60
DEOGEN2	Benign	0.036	T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.38	T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.90	N;D;.;D
REVEL	Benign	0.017
Sift	Benign	0.22	T;D;.;D
Sift4G	Benign	0.47	T;T;.;D
Polyphen		0.0	B;B;.;.
Vest4		0.14
MutPred		0.12		Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);Loss of stability (P = 0.0487);
MVP		0.21
MPC		0.080
ClinPred		0.069	T
GERP RS		-4.5
Varity_R		0.049
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1889074129; hg19: chr15-23811032;