13-23730445-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_005932.4(MIPEP):c.2045G>A(p.Gly682Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00076 in 1,607,416 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (0 hom.)
• Consequence: MIPEP NM_005932.4 missense, splice_region
• Scores: Splicing: ADA: 0.04189
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.71

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]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13435099).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00103 (157/152178) while in subpopulation NFE AF= 0.0019 (129/68034). AF 95% confidence interval is 0.00163. There are 0 homozygotes in gnomad4. There are 64 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MIPEP	NM_005932.4	c.2045G>A	p.Gly682Asp	missense_variant, splice_region_variant	19/19	ENST00000382172.4
LOC105370113	XR_007063722.1	n.651+1168C>T		intron_variant, non_coding_transcript_variant
MIPEP	XM_011535097.3	c.1859G>A	p.Gly620Asp	missense_variant, splice_region_variant	19/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MIPEP	ENST00000382172.4	c.2045G>A	p.Gly682Asp	missense_variant, splice_region_variant	19/19	1	NM_005932.4	P1
	ENST00000691844.2	n.385-4102C>T		intron_variant, non_coding_transcript_variant
MIPEP	ENST00000433710.2	n.238G>A		splice_region_variant, non_coding_transcript_exon_variant	4/4	3
MIPEP	ENST00000464194.3	n.287G>A		splice_region_variant, non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00190

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000697 AC: 171 AN: 245244 Hom.: 0 AF XY: 0.000671 AC XY: 89 AN XY: 132668

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00116

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000732 AC: 1065 AN: 1455238 Hom.: 0 Cov.: 28 AF XY: 0.000761 AC XY: 551 AN XY: 724024

Gnomad4 AFR exome AF: 0.0000905

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.000771

Gnomad4 NFE exome AF: 0.000884

Gnomad4 OTH exome AF: 0.000333

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000861 AC XY: 64 AN XY: 74358

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.00190

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.00138 Hom.: 0

Bravo AF: 0.000801

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000585 AC: 71

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 04, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 02, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 02, 2024	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 682 of the MIPEP protein (p.Gly682Asp). This variant is present in population databases (rs150308123, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with MIPEP-related conditions. ClinVar contains an entry for this variant (Variation ID: 392943). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.40
Cadd	Uncertain	23
Dann	Benign	0.53
DEOGEN2	Benign	0.024	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.030	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.27
Sift	Benign	0.90	T
Sift4G	Benign	0.97	T
Polyphen		0.0	B
Vest4		0.84
MVP		0.57
MPC		0.12
ClinPred		0.032	T
GERP RS		5.4
Varity_R		0.26
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.042
dbscSNV1_RF	Benign	0.45
SpliceAI score (max)		0.020		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: rs150308123; hg19: chr13-24304584;