17-18263230-C-T

Position:

• chr17-18263230-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.292C>T​(p.Pro98Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MIEF2 NM_139162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00

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=0.12482542).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIEF2	NM_139162.4	c.292C>T	p.Pro98Ser	missense_variant	3/4	ENST00000323019.9	NP_631901.2
MIEF2	NM_148886.2	c.325C>T	p.Pro109Ser	missense_variant	3/4		NP_683684.2
MIEF2	NM_001144900.3	c.292C>T	p.Pro98Ser	missense_variant	3/4		NP_001138372.1
MIEF2	XM_017024190.2	c.313C>T	p.Pro105Ser	missense_variant	3/4		XP_016879679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIEF2	ENST00000323019.9	c.292C>T	p.Pro98Ser	missense_variant	3/4	2	NM_139162.4	ENSP00000323591.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461522 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727052

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: 0.0000188

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

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

Jan 26, 2023

The c.325C>T (p.P109S) 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 325, causing the proline (P) at amino acid position 109 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	Benign	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.013	T;.;.;T;T;T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.42	N
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;.;M;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;.;D;N;.;.;N
REVEL	Benign	0.057
Sift	Benign	0.23	T;.;T;T;.;.;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T
Polyphen		0.18	B;.;P;B;.;.;.
Vest4		0.27
MutPred		0.27		Gain of phosphorylation at P98 (P = 0.0117);Gain of phosphorylation at P98 (P = 0.0117);Gain of phosphorylation at P98 (P = 0.0117);Gain of phosphorylation at P98 (P = 0.0117);Gain of phosphorylation at P98 (P = 0.0117);Gain of phosphorylation at P98 (P = 0.0117);.;
MVP		0.28
MPC		0.86
ClinPred		0.33	T
GERP RS		4.1
Varity_R		0.069
gMVP		0.28

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: rs1325074283; hg19: chr17-18166544; COSMIC: COSV58944551; COSMIC: COSV58944551;