17-18263185-C-T

Position:

• chr17-18263185-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_139162.4(MIEF2):​c.247C>T​(p.Arg83Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: MIEF2 NM_139162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.260

Genes affected

MIEF2 (HGNC:17920): (mitochondrial elongation factor 2) This gene encodes an outer mitochondrial membrane protein that functions in the regulation of mitochondrial morphology. It can directly recruit the fission mediator dynamin-related protein 1 (Drp1) to the mitochondrial surface. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

MIEF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21828452).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIEF2	NM_139162.4	c.247C>T	p.Arg83Trp	missense_variant	3/4	ENST00000323019.9	NP_631901.2
MIEF2	NM_148886.2	c.280C>T	p.Arg94Trp	missense_variant	3/4		NP_683684.2
MIEF2	NM_001144900.3	c.247C>T	p.Arg83Trp	missense_variant	3/4		NP_001138372.1
MIEF2	XM_017024190.2	c.268C>T	p.Arg90Trp	missense_variant	3/4		XP_016879679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIEF2	ENST00000323019.9	c.247C>T	p.Arg83Trp	missense_variant	3/4	2	NM_139162.4	ENSP00000323591.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461264 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726926

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.280C>T (p.R94W) alteration is located in exon 3 (coding exon 3) of the MIEF2 gene. This alteration results from a C to T substitution at nucleotide position 280, causing the arginine (R) at amino acid position 94 to be replaced by a tryptophan (W). 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	Benign	0.094
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.;.;T;T;T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.29	N
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.1	M;.;M;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.8	D;.;D;D;.;.;D
REVEL	Benign	0.058
Sift	Uncertain	0.0030	D;.;D;D;.;.;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D
Polyphen		0.99	D;.;D;D;.;.;.
Vest4		0.26
MutPred		0.29		Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);Loss of solvent accessibility (P = 0.0087);.;
MVP		0.41
MPC		0.94
ClinPred		0.94	D
GERP RS		3.3
Varity_R		0.14
gMVP		0.37

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: rs781751638; hg19: chr17-18166499;