3-158644652-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024996.7(GFM1):c.18T>C(p.Ala6=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.538 in 1,572,136 control chromosomes in the GnomAD database, including 230,856 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A6A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.58 (26251 hom., cov: 33)
  • Exomes 𝑓: 0.53 (204605 hom.)
• Consequence: GFM1 NM_024996.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.527

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-158644652-T-C is Benign according to our data. Variant chr3-158644652-T-C is described in ClinVar as [Benign]. Clinvar id is 343919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-158644652-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.527 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFM1	NM_024996.7	c.18T>C	p.Ala6=	synonymous_variant	1/18	ENST00000486715.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFM1	ENST00000486715.6	c.18T>C	p.Ala6=	synonymous_variant	1/18	1	NM_024996.7	P1
GFM1	ENST00000264263.9	c.18T>C	p.Ala6=	synonymous_variant	1/19	5
GFM1	ENST00000478576.5	c.18T>C	p.Ala6=	synonymous_variant	1/14	2
GFM1	ENST00000478254.5	c.18T>C	p.Ala6=	synonymous_variant, NMD_transcript_variant	1/18	5

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87839 AN: 152012 Hom.: 26201 Cov.: 33

Gnomad AFR AF: 0.725

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.539

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.599

Gnomad NFE AF: 0.526

Gnomad OTH AF: 0.556

GnomAD3 exomes AF: 0.543 AC: 98331 AN: 181152 Hom.: 27215 AF XY: 0.545 AC XY: 53213 AN XY: 97550

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.566

Gnomad ASJ exome AF: 0.523

Gnomad EAS exome AF: 0.327

Gnomad SAS exome AF: 0.604

Gnomad FIN exome AF: 0.516

Gnomad NFE exome AF: 0.538

Gnomad OTH exome AF: 0.527

GnomAD4 exome AF: 0.534 AC: 758217 AN: 1420006 Hom.: 204605 Cov.: 45 AF XY: 0.536 AC XY: 376182 AN XY: 702286

Gnomad4 AFR exome AF: 0.736

Gnomad4 AMR exome AF: 0.562

Gnomad4 ASJ exome AF: 0.518

Gnomad4 EAS exome AF: 0.354

Gnomad4 SAS exome AF: 0.604

Gnomad4 FIN exome AF: 0.512

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.540

GnomAD4 genome AF: 0.578 AC: 87945 AN: 152130 Hom.: 26251 Cov.: 33 AF XY: 0.579 AC XY: 43032 AN XY: 74366

Gnomad4 AFR AF: 0.726

Gnomad4 AMR AF: 0.539

Gnomad4 ASJ AF: 0.507

Gnomad4 EAS AF: 0.340

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.529

Gnomad4 NFE AF: 0.526

Gnomad4 OTH AF: 0.561

Alfa AF: 0.549 Hom.: 15187

Bravo AF: 0.584

Asia WGS AF: 0.545 AC: 1894 AN: 3478

ClinVar

Significance: 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, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 18, 2019	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	6.0
Dann	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3

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: rs1864507; hg19: chr3-158362441; COSMIC: COSV51832155; COSMIC: COSV51832155;