rs35942089

Positions:

chr3-158645674-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000486715.6(GFM1):c.127A>G(p.Asn43Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,611,068 control chromosomes in the GnomAD database, including 135 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., cov: 33)

Exomes 𝑓: 0.011 ( 119 hom. )

Consequence

GFM1
ENST00000486715.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 8.87

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008831739).

BP6

Variant 3-158645674-A-G is Benign according to our data. Variant chr3-158645674-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 137462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-158645674-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00889 (1354/152320) while in subpopulation NFE AF= 0.014 (953/68030). AF 95% confidence interval is 0.0133. There are 16 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFM1	NM_024996.7 linkuse as main transcript	c.127A>G	p.Asn43Asp	missense_variant	2/18	ENST00000486715.6	NP_079272.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFM1	ENST00000486715.6 linkuse as main transcript	c.127A>G	p.Asn43Asp	missense_variant	2/18	1	NM_024996.7	ENSP00000419038	P1	Q96RP9-1

Frequencies

GnomAD3 genomes

AF:

0.00890

AC:

1354

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.0237

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00870

Gnomad FIN

AF:

0.00933

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0140

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.00961

AC:

2416

AN:

251432

Hom.:

AF XY:

0.00990

AC XY:

1346

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.00172

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.0204

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00689

Gnomad FIN exome

AF:

0.0109

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.0112

AC:

16352

AN:

1458748

Hom.:

119

Cov.:

AF XY:

0.0115

AC XY:

8325

AN XY:

725894

show subpopulations

Gnomad4 AFR exome

AF:

0.00150

Gnomad4 AMR exome

AF:

0.00369

Gnomad4 ASJ exome

AF:

0.0193

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00762

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.0123

Gnomad4 OTH exome

AF:

0.0101

GnomAD4 genome

AF:

0.00889

AC:

1354

AN:

152320

Hom.:

Cov.:

AF XY:

0.00869

AC XY:

647

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00451

Gnomad4 ASJ

AF:

0.0237

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00870

Gnomad4 FIN

AF:

0.00933

Gnomad4 NFE

AF:

0.0140

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.0133

Hom.:

Bravo

AF:

0.00732

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0101

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.0145

AC:

125

ExAC

AF:

0.00982

AC:

1192

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0122

EpiControl

AF:

0.0100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 24, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 12, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 31, 2023	Variant summary: GFM1 c.127A>G (p.Asn43Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0096 in 251432 control chromosomes, predominantly at a frequency of 0.014 within the Non-Finnish European subpopulation in the gnomAD database, including 14 homozygotes, suggesting a benign role of the gene. c.127A>G has been reported in the literature in individuals affected with unspecified mitochondrial disorder without evidence for causality (Wang_2011). This report does not provide unequivocal conclusions about association of the variant with Hepatoencephalopathy Due To Combined Oxidative Phosphorylation Defect Type 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=5), likely benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GFM1: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.025

T;T;.

Eigen

Benign

-0.0059

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0088

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.1

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.31

N;N;N

REVEL

Benign

0.23

Sift

Benign

0.65

T;T;T

Sift4G

Benign

0.33

T;T;T

Polyphen

0.0040

B;B;.

Vest4

0.68

MVP

0.61

MPC

0.28

ClinPred

0.056

GERP RS

5.4

Varity_R

0.34

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over