rs1057518739

Positions:

• chr13-23806053-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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
• Clinical Significance: Uncertain significance criteria provided, single submitter P:2 U:1
• Conservation: PhyloP100: 8.12

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]

ACMG classification

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/exons	MANE	UniProt
MIPEP	NM_005932.4	c.1745T>G	p.Leu582Arg	missense_variant	16/19	ENST00000382172.4
MIPEP	XM_011535097.3	c.1559T>G	p.Leu520Arg	missense_variant	16/19
MIPEP	XM_011535098.4	c.1745T>G	p.Leu582Arg	missense_variant	16/17
MIPEP	XM_047430368.1	c.1559T>G	p.Leu520Arg	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIPEP	ENST00000382172.4	c.1745T>G	p.Leu582Arg	missense_variant	16/19	1	NM_005932.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461680 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727132

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.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 2016	- -
Pathogenic, no assertion criteria provided	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	-	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

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jun 17, 2015

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	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Pathogenic	3.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.82		Loss of stability (P = 0.0435);
MVP		0.62
MPC		0.58
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs1057518739; hg19: chr13-24380192;