rs150167906

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_005932.4(MIPEP):c.590T>C(p.Leu197Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,599,274 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

MIPEP
NM_005932.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 8.00

Publications

9 publications found

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 Gene-Disease associations (from GenCC):

lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Broad Center for Mendelian Genomics
mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

MIPEP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 13-23874859-A-G is Benign according to our data. Variant chr13-23874859-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 505364.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000814 (124/152352) while in subpopulation NFE AF = 0.00151 (103/68042). AF 95% confidence interval is 0.00128. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIPEP	NM_005932.4 link	c.590T>C	p.Leu197Pro	missense_variant	Exon 5 of 19	ENST00000382172.4	NP_005923.3	Q99797
MIPEP	XM_011535097.3 link	c.404T>C	p.Leu135Pro	missense_variant	Exon 5 of 19		XP_011533399.1
MIPEP	XM_011535098.4 link	c.590T>C	p.Leu197Pro	missense_variant	Exon 5 of 17		XP_011533400.1
MIPEP	XM_047430368.1 link	c.404T>C	p.Leu135Pro	missense_variant	Exon 5 of 17		XP_047286324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIPEP	ENST00000382172.4 link	c.590T>C	p.Leu197Pro	missense_variant	Exon 5 of 19	1	NM_005932.4	ENSP00000371607.3		Q99797

Frequencies

GnomAD3 genomes

AF:

0.000815

AC:

124

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000724

AC:

171

AN:

236292

AF XY:

0.000673

show subpopulations

Gnomad AFR exome

AF:

0.000518

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000234

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.000178

GnomAD4 exome

AF:

0.00153

AC:

2214

AN:

1446922

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1055

AN XY:

719382

show subpopulations

African (AFR)

AF:

0.000400

AC:

AN:

32464

American (AMR)

AF:

0.000242

AC:

AN:

41240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25814

East Asian (EAS)

AF:

0.00

AC:

AN:

38788

South Asian (SAS)

AF:

0.00

AC:

AN:

82544

European-Finnish (FIN)

AF:

0.000263

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00186

AC:

2057

AN:

1107300

Other (OTH)

AF:

0.00201

AC:

120

AN:

59820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

102

204

306

408

510

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

240

320

400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000814

AC:

124

AN:

152352

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000385

AC:

AN:

41572

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00151

AC:

103

AN:

68042

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.000899

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.000708

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Oct 15, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported with a variant on the opposite allele (in trans) in a patient with dilated cardiomyopathy, atelectasis, broad nasal tip, and anteverted nares in the published literature, but this patient also harbored variants in the NKX2-5 and HCN4 genes (PMID: 33587123); Reported as a candidate variant in two individuals with lung cancer, however evidence in support of pathogenicity for this variant was not provided in the report (PMID: 26762739); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 37432431, 26762739, 33587123) -

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 197 of the MIPEP protein (p.Leu197Pro). This variant is present in population databases (rs150167906, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of combined oxidative phosphorylation deficiency (PMID: 33587123). ClinVar contains an entry for this variant (Variation ID: 505364). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MIPEP: BS1, BS2 -

not specified

Uncertain:2

May 02, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: MIPEP c.590T>C (p.Leu197Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00072 in 236292 control chromosomes. c.590T>C has been reported in the literature in at least one compound heterozygous infant affected with clinical features that include atrial septal defect, atrioventricular conduction defects, bradycardia, cardiomyopathy, combined oxidative phosphorylation deficiency-31 who also carried an additional HCN4 variant of uncertain significance (e.g. Maron_2021). This report does not provide unequivocal conclusions about association of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 33587123). ClinVar contains an entry for this variant (Variation ID: 505364). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nov 05, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Leu197Pro variant has not been previously associated with disease, though it was identified in 2 Chinese individuals in a lung cancer GWAS study (Liu 201 6). This variant has also been identified in 0.1% (76/66366) of European chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs150167906). Computational prediction tools and conservation analysis sug gest that the variant would impact the protein, though this information is not p redictive enough to determine pathogenicity. Additionally, currently there are n o known disease associations to the MIPEP gene. In summary, the clinical signifi cance of the p.Leu197Pro variant is uncertain. -

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

Uncertain:1

Feb 23, 2023

3billion

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.071%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.73; 3Cnet: 0.72). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases

Benign:1

Oct 22, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.047

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.61

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.69

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

3.6

PhyloP100

8.0

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.4

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MVP

0.61

MPC

0.61

ClinPred

0.27

GERP RS

5.7

Varity_R

0.93

gMVP

0.97

Mutation Taster

=1/99

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.24

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.24

Position offset: 50

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over