chr15-23566139-C-G

Variant names:

• chr15-23566139-C-G
• rs199845546
• NM_005664.4:c.357C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005664.4(MKRN3):​c.357C>G​(p.His119Gln) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H119H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MKRN3 NM_005664.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.32
• Publications: 0 publications found

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]

MKRN3 Gene-Disease associations (from GenCC):

• precocious puberty, central, 2

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000260978 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005664.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKRN3	NM_005664.4	MANE Select	c.357C>G	p.His119Gln	missense	Exon 1 of 1	NP_005655.1	Q13064

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MKRN3	ENST00000314520.6	TSL:6 MANE Select	c.357C>G	p.His119Gln	missense	Exon 1 of 1	ENSP00000313881.3	Q13064
	MKRN3	ENST00000568252.1	TSL:1	c.305+52C>G		intron	N/A	ENSP00000456779.1	Q6NSB6
	MKRN3	ENST00000676568.1		c.357C>G	p.His119Gln	missense	Exon 1 of 2	ENSP00000502884.1	A0A7I2YQ72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		-1.3
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.74		Loss of catalytic residue at L121 (P = 0.0698)
MVP		0.82
MPC		0.40
ClinPred		0.99	D
GERP RS		-3.9
PromoterAI		-0.0035	Neutral
Varity_R		0.82
gMVP		0.86

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

Other links and lift over

dbSNP: rs199845546; hg19: chr15-23811286;