rs753252850

Positions:

chr13-23809899-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_005932.4(MIPEP):c.1679G>A(p.Arg560His) variant causes a missense change. The variant allele was found at a frequency of 0.0000422 in 1,613,162 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

MIPEP
NM_005932.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.32

Variant links:

Genes affected

MIPEP (HGNC:7104): (mitochondrial intermediate peptidase) The product of this gene performs the final step in processing a specific class of nuclear-encoded proteins targeted to the mitochondrial matrix or inner membrane. This protein is primarily involved in the maturation of oxidative phosphorylation (OXPHOS)-related proteins. This gene may contribute to the functional effects of frataxin deficiency and the clinical manifestations of Friedreich ataxia. [provided by RefSeq, Jul 2008]

MIPEP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIPEP	NM_005932.4 linkuse as main transcript	c.1679G>A	p.Arg560His	missense_variant	15/19	ENST00000382172.4	NP_005923.3	Q99797
MIPEP	XM_011535097.3 linkuse as main transcript	c.1493G>A	p.Arg498His	missense_variant	15/19		XP_011533399.1
MIPEP	XM_011535098.4 linkuse as main transcript	c.1679G>A	p.Arg560His	missense_variant	15/17		XP_011533400.1
MIPEP	XM_047430368.1 linkuse as main transcript	c.1493G>A	p.Arg498His	missense_variant	15/17		XP_047286324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIPEP	ENST00000382172.4 linkuse as main transcript	c.1679G>A	p.Arg560His	missense_variant	15/19	1	NM_005932.4	ENSP00000371607.3		Q99797

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000478

AC:

AN:

251236

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000981

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000445

AC:

AN:

1461130

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000928

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.1679G>A (p.R560H) alteration is located in exon 15 (coding exon 15) of the MIPEP gene. This alteration results from a G to A substitution at nucleotide position 1679, causing the arginine (R) at amino acid position 560 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Aug 07, 2018

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 560 of the MIPEP protein (p.Arg560His). This variant is present in population databases (rs753252850, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MIPEP-related conditions. ClinVar contains an entry for this variant (Variation ID: 587593). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MIPEP protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.076

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0048

MetaRNN

Pathogenic

0.80

MetaSVM

Benign

-1.3

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-2.3

REVEL

Uncertain

0.31

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.014

Polyphen

0.98

Vest4

0.81

MutPred

0.64

Gain of ubiquitination at K555 (P = 0.034);

MVP

0.66

MPC

0.26

ClinPred

0.17

GERP RS

6.0

Varity_R

0.46

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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