13-23756598-C-A

Variant names:

• chr13-23756598-C-A
• rs746768958
• NM_005932.4:c.1991G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005932.4(MIPEP):​c.1991G>T​(p.Arg664Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R664H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MIPEP NM_005932.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84
• Publications: 2 publications found

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: Broad Center for Mendelian Genomics, Labcorp Genetics (formerly Invitae), Orphanet
• mitochondrial disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005932.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIPEP	NM_005932.4	MANE Select	c.1991G>T	p.Arg664Leu	missense	Exon 18 of 19	NP_005923.3	Q99797

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIPEP	ENST00000382172.4	TSL:1 MANE Select	c.1991G>T	p.Arg664Leu	missense	Exon 18 of 19	ENSP00000371607.3	Q99797
	MIPEP	ENST00000906723.1		c.1952G>T	p.Arg651Leu	missense	Exon 18 of 19	ENSP00000576782.1
	MIPEP	ENST00000906727.1		c.1913G>T	p.Arg638Leu	missense	Exon 17 of 18	ENSP00000576786.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.8
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.022	D
Polyphen		0.98	D
Vest4		0.92
MutPred		0.68		Loss of disorder (P = 0.0359)
MVP		0.49
MPC		0.53
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.74
gMVP		0.88
Mutation Taster		=28/72	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs746768958; hg19: chr13-24330737;