Variant 15-23565696-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_005664.4(MKRN3):c.-87C>T variant causes a 5 prime UTR 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0035 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0038 ( 15 hom. )

Consequence

MKRN3
NM_005664.4 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.15

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 528 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKRN3	NM_005664.4 linkuse as main transcript	c.-87C>T		5_prime_UTR_variant	1/1	ENST00000314520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKRN3	ENST00000314520.6 linkuse as main transcript	c.-87C>T		5_prime_UTR_variant	1/1		NM_005664.4	P1
	ENST00000563044.2 linkuse as main transcript	n.2134G>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes

AF:

0.00347

AC:

528

AN:

152156

Hom.:

Cov.:

show subpopulations

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.:

Cov.:

AF XY:

0.00369

AC XY:

2156

AN XY:

584688

show subpopulations

Gnomad4 AFR exome

AF:

0.000603

Gnomad4 AMR exome

AF:

0.000539

Gnomad4 ASJ exome

AF:

0.0000540

Gnomad4 EAS exome

AF:

0.000904

Gnomad4 SAS exome

AF:

0.000231

Gnomad4 FIN exome

AF:

0.0117

Gnomad4 NFE exome

AF:

0.00413

Gnomad4 OTH exome

AF:

0.00231

GnomAD4 genome

AF:

0.00347

AC:

528

AN:

152274

Hom.:

Cov.:

AF XY:

0.00365

AC XY:

272

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.000784

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00135

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00971

Gnomad4 NFE

AF:

0.00550

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00293

Hom.:

Bravo

AF:

0.00260

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 10, 2022

Reported as g.+13C>T using alternate nomenclature and observed as a paternally inherited heterozygous variant in a patient with central precocious puberty in published literature (Fanis et al., 2019); Published functional studies suggest this variant has a negative effect on gene regulation, however additional studies are needed to validate the functional effect of this variant in vivo (Fanis et al., 2019); Located in the 5' UTR region of the gene; Nucleotide substitution has no predicted effect on splicing and is not conserved across species; This variant is associated with the following publications: (PMID: 34426522, 31636607) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.81

DANN

Benign

0.73

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over