Variant 7-140479286-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_013446.4(MKRN1):c.59C>A(p.Ala20Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000788 in 1,387,470 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00082 ( 0 hom. )

Consequence

MKRN1
NM_013446.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.96

Variant links:

Genes affected

MKRN1 (HGNC:7112): (makorin ring finger protein 1) This gene encodes a protein that belongs to a novel class of zinc finger proteins. The encoded protein functions as a transcriptional co-regulator, and as an E3 ubiquitin ligase that promotes the ubiquitination and proteasomal degradation of target proteins. The protein encoded by this gene is thought to regulate RNA polymerase II-catalyzed transcription. Substrates for this protein's E3 ubiquitin ligase activity include the capsid protein of the West Nile virus and the catalytic subunit of the telomerase ribonucleoprotein. This protein controls cell cycle arrest and apoptosis by regulating p21, a cell cycle regulator, and the tumor suppressor protein p53. Pseudogenes of this gene are present on chromosomes 1, 3, 9, 12 and 20, and on the X chromosome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Apr 2014]

MKRN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.014960676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MKRN1	NM_013446.4 linkuse as main transcript	c.59C>A	p.Ala20Glu	missense_variant	1/8	ENST00000255977.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MKRN1	ENST00000255977.7 linkuse as main transcript	c.59C>A	p.Ala20Glu	missense_variant	1/8	1	NM_013446.4		Q9UHC7-1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000853

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000986

AC:

AN:

30434

Hom.:

AF XY:

0.000650

AC XY:

AN XY:

15386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00198

Gnomad NFE exome

AF:

0.000962

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000818

AC:

1010

AN:

1235286

Hom.:

Cov.:

AF XY:

0.000788

AC XY:

474

AN XY:

601460

show subpopulations

Gnomad4 AFR exome

AF:

0.0000834

Gnomad4 AMR exome

AF:

0.000169

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00176

Gnomad4 NFE exome

AF:

0.000897

Gnomad4 OTH exome

AF:

0.000600

GnomAD4 genome

AF:

0.000552

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000672

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000942

Gnomad4 NFE

AF:

0.000853

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.0000530

Hom.:

Bravo

AF:

0.000521

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000528

AC:

ExAC

AF:

0.000476

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.59C>A (p.A20E) alteration is located in exon 1 (coding exon 1) of the MKRN1 gene. This alteration results from a C to A substitution at nucleotide position 59, causing the alanine (A) at amino acid position 20 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.083

T;.

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.015

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.51

N;N

REVEL

Benign

0.048

Sift

Benign

0.20

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.28

B;.

Vest4

0.33

MVP

0.35

MPC

0.16

ClinPred

0.11

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.14

gMVP

0.34

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