22-39513721-G-A

Variant names:

• chr22-39513721-G-A
• rs2232091
• NM_019008.6:c.790G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_019008.6(MIEF1):​c.790G>A​(p.Asp264Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00875 in 1,614,212 control chromosomes in the GnomAD database, including 94 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0062 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0090 (89 hom.)
• Consequence: MIEF1 NM_019008.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066976547).
• BS2: High AC in GnomAd4 at 941 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIEF1	NM_019008.6	c.790G>A	p.Asp264Asn	missense_variant	Exon 6 of 6	ENST00000325301.7	NP_061881.2
MIEF1	NM_001304564.2	c.790G>A	p.Asp264Asn	missense_variant	Exon 6 of 7		NP_001291493.1
MIEF1	NR_130789.2	n.1191G>A		non_coding_transcript_exon_variant	Exon 6 of 6
MIEF1	NR_130790.2	n.1341G>A		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIEF1	ENST00000325301.7	c.790G>A	p.Asp264Asn	missense_variant	Exon 6 of 6	1	NM_019008.6	ENSP00000327124.2

Frequencies

GnomAD3 genomes AF: 0.00619 AC: 943 AN: 152224 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00594 AC: 1493 AN: 251320 AF XY: 0.00623

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00499

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00902 AC: 13190 AN: 1461870 Hom.: 89 Cov.: 31 AF XY: 0.00882 AC XY: 6415 AN XY: 727236

Gnomad4 AFR exome AF: 0.00128 AC: 43 AN: 33478

Gnomad4 AMR exome AF: 0.00215 AC: 96 AN: 44722

Gnomad4 ASJ exome AF: 0.000727 AC: 19 AN: 26136

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39698

Gnomad4 SAS exome AF: 0.00378 AC: 326 AN: 86256

Gnomad4 FIN exome AF: 0.00490 AC: 262 AN: 53420

Gnomad4 NFE exome AF: 0.0109 AC: 12069 AN: 1111996

Gnomad4 Remaining exome AF: 0.00609 AC: 368 AN: 60396

GnomAD4 genome AF: 0.00618 AC: 941 AN: 152342 Hom.: 5 Cov.: 32 AF XY: 0.00557 AC XY: 415 AN XY: 74494

Gnomad4 AFR AF: 0.00173 AC: 0.00173177 AN: 0.00173177

Gnomad4 AMR AF: 0.00411 AC: 0.00411442 AN: 0.00411442

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00456 AC: 0.00455675 AN: 0.00455675

Gnomad4 FIN AF: 0.00443 AC: 0.00442728 AN: 0.00442728

Gnomad4 NFE AF: 0.0106 AC: 0.0106274 AN: 0.0106274

Gnomad4 OTH AF: 0.00615 AC: 0.00614948 AN: 0.00614948

Alfa AF: 0.00871 Hom.: 22

Bravo AF: 0.00607

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.0109 AC: 42

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.00620 AC: 753

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00938

EpiControl AF: 0.00937

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Retinal dystrophy Uncertain:1

Jan 01, 2022

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.68
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.71	T;.;T
MetaRNN	Benign	0.0067	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.11	.;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.72	P;B;B
Vest4		0.31
MVP		0.51
MPC		0.40
ClinPred		0.044	T
GERP RS		6.1
Varity_R		0.17
gMVP		0.26
Mutation Taster		=99/1	polymorphism

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: rs2232091; hg19: chr22-39909726; COSMIC: COSV57478525; COSMIC: COSV57478525;