Genetic Variant NM_005932.4:c.1745T>G (chr13-23806053-A-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_005932.4(MIPEP):c.1745T>G(p.Leu582Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,680 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: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MIPEP
NM_005932.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:2U:1

Conservation

PhyloP100: 8.12

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIPEP	NM_005932.4 link	c.1745T>G	p.Leu582Arg	missense_variant	Exon 16 of 19	ENST00000382172.4	NP_005923.3	Q99797
MIPEP	XM_011535097.3 link	c.1559T>G	p.Leu520Arg	missense_variant	Exon 16 of 19		XP_011533399.1
MIPEP	XM_011535098.4 link	c.1745T>G	p.Leu582Arg	missense_variant	Exon 16 of 17		XP_011533400.1
MIPEP	XM_047430368.1 link	c.1559T>G	p.Leu520Arg	missense_variant	Exon 16 of 17		XP_047286324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIPEP	ENST00000382172.4 link	c.1745T>G	p.Leu582Arg	missense_variant	Exon 16 of 19	1	NM_005932.4	ENSP00000371607.3		Q99797

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461680

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Pathogenic:2

Dec 01, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

This variant was detected as compound heterozygous in an individual with left ventricular noncompaction, developmental delay, hypotonia, and death during infancy. -

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

Uncertain:1

Jun 17, 2015

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Possible pathogenicity based on finding it once in our laboratory in trans with another variant (c.212T>A; p.Leu71Gln) in a 10-month-old male with left ventricular noncompaction, global delays, hypotonia, hypertonia/spasticity, abnormal movements, dysmorphic features, short stature, microcephaly, failure to thrive -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

3.4

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-4.6

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.99

MutPred

0.82

Loss of stability (P = 0.0435);

MVP

0.62

MPC

0.58

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.94

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