rs199845546

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr15-23566139-C-T
• chr15-23566139-C-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005664.4(MKRN3):​c.357C>T​(p.His119His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000966 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00047 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: MKRN3 NM_005664.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.32
• Publications: 1 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-23566139-C-T is Benign according to our data. Variant chr15-23566139-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 731888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000466 (71/152352) while in subpopulation AMR AF = 0.00451 (69/15304). AF 95% confidence interval is 0.00365. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 71 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.357C>T	p.His119His	synonymous	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>T	p.His119His	synonymous	Exon 1 of 1	ENSP00000313881.3	Q13064
	MKRN3	ENST00000568252.1	TSL:1	c.305+52C>T		intron	N/A	ENSP00000456779.1	Q6NSB6
	MKRN3	ENST00000676568.1		c.357C>T	p.His119His	synonymous	Exon 1 of 2	ENSP00000502884.1	A0A7I2YQ72

Frequencies

GnomAD3 genomes AF: 0.000466 AC: 71 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000239 AC: 60 AN: 251216 AF XY: 0.000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000581 AC: 85 AN: 1461770 Hom.: 0 Cov.: 30 AF XY: 0.0000660 AC XY: 48 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00132 AC: 59 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111974

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.000466 AC: 71 AN: 152352 Hom.: 0 Cov.: 33 AF XY: 0.000738 AC XY: 55 AN XY: 74504

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00451 AC: 69 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000565 Hom.: 0

Bravo AF: 0.000533

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	MKRN3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	3.1
DANN	Benign	0.93
PhyloP100		-1.3
PromoterAI		0.028	Neutral

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: rs199845546; hg19: chr15-23811286; COSMIC: COSV58810706; COSMIC: COSV58810706;