rs1057518741

Positions:

• chr13-23862328-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005932.4(MIPEP):​c.1027A>G​(p.Lys343Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,326 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: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: MIPEP NM_005932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.05

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIPEP	NM_005932.4	c.1027A>G	p.Lys343Glu	missense_variant	9/19	ENST00000382172.4	NP_005923.3
MIPEP	XM_011535097.3	c.841A>G	p.Lys281Glu	missense_variant	9/19		XP_011533399.1
MIPEP	XM_011535098.4	c.1027A>G	p.Lys343Glu	missense_variant	9/17		XP_011533400.1
MIPEP	XM_047430368.1	c.841A>G	p.Lys281Glu	missense_variant	9/17		XP_047286324.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIPEP	ENST00000382172.4	c.1027A>G	p.Lys343Glu	missense_variant	9/19	1	NM_005932.4	ENSP00000371607	P1
MIPEP	ENST00000494139.1	n.424A>G		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432326 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 712010

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: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal left ventricular non-compaction-seizures-hypotonia-cataract-developmental delay syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2016

- -

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 homozygous in a 10-month-old male with global delays, hypotonia, mild opisthotonus, slightly dysmorphic, acquired microcephaly, failure to thrive, vision loss, small ASD secundum with left to right shunt and moderate left ventricular hypertrophy without left ventricular outflow obstruction. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.024	T
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.98	D
Vest4		0.70
MutPred		0.78		Loss of MoRF binding (P = 0.008);
MVP		0.59
MPC		0.53
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.86

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: rs1057518741; hg19: chr13-24436467;