chr3-158690243-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024996.7(GFM1):c.1990G>A(p.Val664Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,613,648 control chromosomes in the GnomAD database, including 331 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 26 hom., cov: 33)

Exomes 𝑓: 0.018 ( 305 hom. )

Consequence

GFM1
NM_024996.7 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.64

Publications

10 publications found

Variant links:

Genes affected

GFM1 (HGNC:13780): (G elongation factor mitochondrial 1) Eukaryotes contain two protein translational systems, one in the cytoplasm and one in the mitochondria. Mitochondrial translation is crucial for maintaining mitochondrial function and mutations in this system lead to a breakdown in the respiratory chain-oxidative phosphorylation system and to impaired maintenance of mitochondrial DNA. This gene encodes one of the mitochondrial translation elongation factors. Its role in the regulation of normal mitochondrial function and in different disease states attributed to mitochondrial dysfunction is not known. [provided by RefSeq, Jul 2008]

GFM1 Gene-Disease associations (from GenCC):

hepatoencephalopathy due to combined oxidative phosphorylation defect type 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
Leigh syndrome
Inheritance: AR Classification: MODERATE Submitted by: ClinGen

GFM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044956803).

BP6

Variant 3-158690243-G-A is Benign according to our data. Variant chr3-158690243-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0146 (2220/152114) while in subpopulation NFE AF = 0.0186 (1267/68006). AF 95% confidence interval is 0.0178. There are 26 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFM1	NM_024996.7 link	c.1990G>A	p.Val664Ile	missense_variant	Exon 16 of 18	ENST00000486715.6	NP_079272.4	Q96RP9-1E5KND5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFM1	ENST00000486715.6 link	c.1990G>A	p.Val664Ile	missense_variant	Exon 16 of 18	1	NM_024996.7	ENSP00000419038.1		Q96RP9-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2220

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.0175

Gnomad AMR

AF:

0.00747

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00685

Gnomad FIN

AF:

0.0591

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0186

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0168

AC:

4231

AN:

251444

AF XY:

0.0172

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00497

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0586

Gnomad NFE exome

AF:

0.0207

Gnomad OTH exome

AF:

0.0148

GnomAD4 exome

AF:

0.0178

AC:

25963

AN:

1461534

Hom.:

305

Cov.:

AF XY:

0.0177

AC XY:

12897

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00272

AC:

AN:

33474

American (AMR)

AF:

0.00452

AC:

202

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00731

AC:

191

AN:

26128

East Asian (EAS)

AF:

0.000151

AC:

AN:

39684

South Asian (SAS)

AF:

0.00821

AC:

708

AN:

86256

European-Finnish (FIN)

AF:

0.0557

AC:

2976

AN:

53416

Middle Eastern (MID)

AF:

0.00625

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0188

AC:

20848

AN:

1111706

Other (OTH)

AF:

0.0150

AC:

905

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1422

2845

4267

5690

7112

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

756

1512

2268

3024

3780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0146

AC:

2220

AN:

152114

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1190

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00280

AC:

116

AN:

41502

American (AMR)

AF:

0.00746

AC:

114

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00778

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5174

South Asian (SAS)

AF:

0.00664

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0591

AC:

623

AN:

10548

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0186

AC:

1267

AN:

68006

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0152

Hom.:

Bravo

AF:

0.0106

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0203

AC:

175

ExAC

AF:

0.0177

AC:

2148

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 06, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Apr 09, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, gene associated with combined oxidative phosphorylation deficiency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.030

T;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0045

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.6

L;.

PhyloP100

7.6

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.73

N;N

REVEL

Benign

0.18

Sift

Benign

0.33

T;T

Sift4G

Benign

0.31

T;T

Polyphen

0.76

P;P

Vest4

0.23

MPC

0.29

ClinPred

0.025

GERP RS

5.8

Varity_R

0.13

gMVP

0.67

Mutation Taster

=97/3

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over