rs779598020

Positions:

chr13-23837561-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_005932.4(MIPEP):c.1534C>G(p.His512Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000931 in 1,610,352 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

MIPEP
NM_005932.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.61

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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

PP5

Variant 13-23837561-G-C is Pathogenic according to our data. Variant chr13-23837561-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208633.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MIPEP	NM_005932.4 linkuse as main transcript	c.1534C>G	p.His512Asp	missense_variant	13/19	ENST00000382172.4	NP_005923.3
MIPEP	XM_011535097.3 linkuse as main transcript	c.1348C>G	p.His450Asp	missense_variant	13/19		XP_011533399.1
MIPEP	XM_011535098.4 linkuse as main transcript	c.1534C>G	p.His512Asp	missense_variant	13/17		XP_011533400.1
MIPEP	XM_047430368.1 linkuse as main transcript	c.1348C>G	p.His450Asp	missense_variant	13/17		XP_047286324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIPEP	ENST00000382172.4 linkuse as main transcript	c.1534C>G	p.His512Asp	missense_variant	13/19	1	NM_005932.4	ENSP00000371607	P1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251284

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135806

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:

0.00

Gnomad NFE exome

AF:

0.0000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000960

AC:

140

AN:

1458108

Hom.:

Cov.:

AF XY:

0.0000828

AC XY:

AN XY:

724820

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000121

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Sep 30, 2019	This variant has been previously reported in trans configuration with a 1.4-Mb deletion of 13q12.12 that included MIPEP gene in a patient with respiratory depression at birth, seizures, arrrhythmia, cardiac abnormalities (biventricular hypertrophic cardiomyopathy, patent ductus arteriosis, ventricular septal defect, congestive heart failure), lactic acidosis, congenital hyperinsulinemia, abnormal blood gases, microcolon, dysmorphic facial features, and abnormal light and electron microscopic findings of the skeletal muscle (diaphragm) and cardiac muscle (PMID: 27799064). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.004% (12/277042), is absent in the homozygous state, and thus is presumed to be rare. This variant has been reported in the ClinVar database (Variation ID: 208633). The c.1534C>G (p.His512Asp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.1534C>G (p.His512Asp) variant is classified as Likely Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology	-	PS4, PM1, PM3, PP3 -

Cardiomyopathy;C1860834:Infantile muscular hypotonia;C1960469:Left ventricular noncompaction

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Baylor Genetics

Jun 17, 2015

This variant was reported once (from another laboratory) in trans with a gene deletion in a deceased 19-day-old male with seizures, severe biventricular hypertrophic cardiomyopathy, dysmorphic features, congenital hyperinsulinemia, lactic acidosis, microcolon, rhombencephalosynapsis, small VSD, similarly affected sib (not tested) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.90

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.9

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.010

Polyphen

1.0

Vest4

0.96

MVP

0.70

MPC

0.56

ClinPred

0.94

GERP RS

5.8

Varity_R

0.96

gMVP

0.85

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