15-23565696-C-T

Variant names:

• chr15-23565696-C-T
• rs184950120
• NM_005664.4:c.-87C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005664.4(MKRN3):​c.-87C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,352,092 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (15 hom.)
• Consequence: MKRN3 NM_005664.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -3.15
• Publications: 8 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-23565696-C-T is Benign according to our data. Variant chr15-23565696-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2497936.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00347 (528/152274) while in subpopulation NFE AF = 0.0055 (374/68020). AF 95% confidence interval is 0.00504. There are 3 homozygotes in GnomAd4. There are 272 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 528 AD gene.

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.-87C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	NP_005655.1	Q13064
	MKRN3	NM_005664.4	MANE Select	c.-87C>T		5_prime_UTR	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.-87C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 1	ENSP00000313881.3	Q13064
	MKRN3	ENST00000314520.6	TSL:6 MANE Select	c.-87C>T		5_prime_UTR	Exon 1 of 1	ENSP00000313881.3	Q13064
	MKRN3	ENST00000564592.2	TSL:3	c.-87C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000455368.1	H3BPL3

Frequencies

GnomAD3 genomes AF: 0.00347 AC: 528 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00971

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00550

Gnomad OTH AF: 0.00192

GnomAD4 exome AF: 0.00378 AC: 4536 AN: 1199818 Hom.: 15 Cov.: 18 AF XY: 0.00369 AC XY: 2156 AN XY: 584688

African (AFR) AF: 0.000603 AC: 16 AN: 26516

American (AMR) AF: 0.000539 AC: 11 AN: 20392

Ashkenazi Jewish (ASJ) AF: 0.0000540 AC: 1 AN: 18512

East Asian (EAS) AF: 0.000904 AC: 31 AN: 34284

South Asian (SAS) AF: 0.000231 AC: 14 AN: 60602

European-Finnish (FIN) AF: 0.0117 AC: 421 AN: 35842

Middle Eastern (MID) AF: 0.000287 AC: 1 AN: 3480

European-Non Finnish (NFE) AF: 0.00413 AC: 3924 AN: 949646

Other (OTH) AF: 0.00231 AC: 117 AN: 50544

GnomAD4 genome AF: 0.00347 AC: 528 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74450

African (AFR) AF: 0.000625 AC: 26 AN: 41578

American (AMR) AF: 0.000784 AC: 12 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00971 AC: 103 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00550 AC: 374 AN: 68020

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00293 Hom.: 0

Bravo AF: 0.00260

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.81
DANN	Benign	0.73
PhyloP100		-3.1
PromoterAI		-0.14	Neutral
Mutation Taster		=299/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs184950120; hg19: chr15-23810843; COSMIC: COSV100090633; COSMIC: COSV100090633;