rs62288347

Positions:

• chr3-158690243-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 137466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-158690243-G-A is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFM1	NM_024996.7	c.1990G>A	p.Val664Ile	missense_variant	16/18	ENST00000486715.6	NP_079272.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFM1	ENST00000486715.6	c.1990G>A	p.Val664Ile	missense_variant	16/18	1	NM_024996.7	ENSP00000419038	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2220 AN: 151996 Hom.: 26 Cov.: 33

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

GnomAD3 exomes AF: 0.0168 AC: 4231 AN: 251444 Hom.: 77 AF XY: 0.0172 AC XY: 2336 AN XY: 135894

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 SAS exome AF: 0.00725

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.: 32 AF XY: 0.0177 AC XY: 12897 AN XY: 727104

Gnomad4 AFR exome AF: 0.00272

Gnomad4 AMR exome AF: 0.00452

Gnomad4 ASJ exome AF: 0.00731

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00821

Gnomad4 FIN exome AF: 0.0557

Gnomad4 NFE exome AF: 0.0188

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0146 AC: 2220 AN: 152114 Hom.: 26 Cov.: 33 AF XY: 0.0160 AC XY: 1190 AN XY: 74354

Gnomad4 AFR AF: 0.00280

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00664

Gnomad4 FIN AF: 0.0591

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0162 Hom.: 27

Bravo AF: 0.0106

TwinsUK AF: 0.0186 AC: 69

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0203 AC: 175

ExAC AF: 0.0177 AC: 2148

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hepatoencephalopathy due to combined oxidative phosphorylation defect type 1 Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 06, 2019	- -
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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 09, 2013	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. -
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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
MetaRNN	Benign	0.0045	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
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	T
GERP RS		5.8
Varity_R		0.13
gMVP		0.67

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

LitVar

Other links and lift over

dbSNP: rs62288347; hg19: chr3-158408032;