13-23730388-A-G

Position:

• chr13-23730388-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005932.4(MIPEP):​c.2102T>C​(p.Leu701Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MIPEP NM_005932.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.73

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]

ENSG00000289332 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIPEP	NM_005932.4	c.2102T>C	p.Leu701Ser	missense_variant	19/19	ENST00000382172.4	NP_005923.3
MIPEP	XM_011535097.3	c.1916T>C	p.Leu639Ser	missense_variant	19/19		XP_011533399.1
LOC105370113	XR_007063722.1	n.651+1111A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIPEP	ENST00000382172.4	c.2102T>C	p.Leu701Ser	missense_variant	19/19	1	NM_005932.4	ENSP00000371607.3
MIPEP	ENST00000433710.2	n.295T>C		non_coding_transcript_exon_variant	4/4	3
MIPEP	ENST00000464194.3	n.344T>C		non_coding_transcript_exon_variant	2/2	2
ENSG00000289332	ENST00000691844.2	n.385-4159A>G		intron_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2024

The c.2102T>C (p.L701S) alteration is located in exon 19 (coding exon 19) of the MIPEP gene. This alteration results from a T to C substitution at nucleotide position 2102, causing the leucine (L) at amino acid position 701 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.014	T
MetaRNN	Pathogenic	0.82	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.86	P
Vest4		0.84
MutPred		0.55		Gain of relative solvent accessibility (P = 0.0027);
MVP		0.45
MPC		0.43
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.32
gMVP		0.75

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: rs1593120150; hg19: chr13-24304527;