22-39512340-G-T

Variant names:

• chr22-39512340-G-T
• rs777054252
• NM_019008.6:c.431G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_019008.6(MIEF1):​c.431G>T​(p.Arg144Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R144P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MIEF1 NM_019008.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.44
• Publications: 6 publications found

Genes affected

MIEF1 (HGNC:25979): (mitochondrial elongation factor 1) Enables ADP binding activity; GDP binding activity; and identical protein binding activity. Involved in several processes, including positive regulation of mitochondrial fission; positive regulation of mitochondrial translation; and positive regulation of protein targeting to membrane. Located in mitochondrial matrix and mitochondrial outer membrane. Colocalizes with mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Apr 2022]

MIEF1 Gene-Disease associations (from GenCC):

• optic atrophy 14

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39358425).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019008.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIEF1	NM_019008.6	MANE Select	c.431G>T	p.Arg144Leu	missense	Exon 5 of 6	NP_061881.2
	MIEF1	NM_001304564.2		c.431G>T	p.Arg144Leu	missense	Exon 5 of 7	NP_001291493.1	B0QY95
	MIEF1	NR_130789.2		n.832G>T		non_coding_transcript_exon	Exon 5 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIEF1	ENST00000325301.7	TSL:1 MANE Select	c.431G>T	p.Arg144Leu	missense	Exon 5 of 6	ENSP00000327124.2	Q9NQG6-1
	MIEF1	ENST00000402881.5	TSL:1	c.431G>T	p.Arg144Leu	missense	Exon 5 of 7	ENSP00000385110.1	B0QY95
	MIEF1	ENST00000433117.6	TSL:1	n.345G>T		non_coding_transcript_exon	Exon 5 of 6	ENSP00000404096.2	Q9NQG6-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		7.4
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.15
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.057	T
Polyphen		0.72	P
Vest4		0.68
MutPred		0.33		Loss of MoRF binding (P = 0.0402)
MVP		0.32
MPC		0.55
ClinPred		0.95	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.67
gMVP		0.33
Mutation Taster		=26/74	disease causing

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

Other links and lift over

dbSNP: rs777054252; hg19: chr22-39908345;