chr17-18263168-C-T

Position:

• chr17-18263168-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.230C>T​(p.Thr77Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: MIEF2 NM_139162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23

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=0.103219986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIEF2	NM_139162.4	c.230C>T	p.Thr77Ile	missense_variant	3/4	ENST00000323019.9	NP_631901.2
MIEF2	NM_148886.2	c.263C>T	p.Thr88Ile	missense_variant	3/4		NP_683684.2
MIEF2	NM_001144900.3	c.230C>T	p.Thr77Ile	missense_variant	3/4		NP_001138372.1
MIEF2	XM_017024190.2	c.251C>T	p.Thr84Ile	missense_variant	3/4		XP_016879679.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIEF2	ENST00000323019.9	c.230C>T	p.Thr77Ile	missense_variant	3/4	2	NM_139162.4	ENSP00000323591.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Mar 06, 2023

The c.263C>T (p.T88I) 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 263, causing the threonine (T) at amino acid position 88 to be replaced by an isoleucine (I). 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	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;.;.;T;T;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.24	N
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M;.;M;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N;.;D;D;.;.;N
REVEL	Benign	0.065
Sift	Uncertain	0.0090	D;.;D;D;.;.;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D
Polyphen		0.16	B;.;B;B;.;.;.
Vest4		0.32
MutPred		0.26		Loss of glycosylation at T77 (P = 0.0224);Loss of glycosylation at T77 (P = 0.0224);Loss of glycosylation at T77 (P = 0.0224);Loss of glycosylation at T77 (P = 0.0224);Loss of glycosylation at T77 (P = 0.0224);Loss of glycosylation at T77 (P = 0.0224);.;
MVP		0.27
MPC		0.41
ClinPred		0.65	D
GERP RS		3.4
Varity_R		0.078
gMVP		0.52

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: rs1978512657; hg19: chr17-18166482;