3-158644604-A-G

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.-31A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.003 in 1,550,486 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (83 hom.)
• Consequence: GFM1 NM_024996.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.50

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 (BayesDel_noAF=-0.9).
• BP6: Variant 3-158644604-A-G is Benign according to our data. Variant chr3-158644604-A-G is described in ClinVar as [Benign]. Clinvar id is 137469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-158644604-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00445 (678/152332) while in subpopulation EAS AF= 0.0474 (246/5186). AF 95% confidence interval is 0.0426. There are 8 homozygotes in gnomad4. There are 423 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFM1	NM_024996.7	c.-31A>G		5_prime_UTR_variant	1/18	ENST00000486715.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFM1	ENST00000486715.6	c.-31A>G		5_prime_UTR_variant	1/18	1	NM_024996.7	P1
GFM1	ENST00000264263.9	c.-31A>G		5_prime_UTR_variant	1/19	5
GFM1	ENST00000478576.5	c.-31A>G		5_prime_UTR_variant	1/14	2
GFM1	ENST00000478254.5	c.-31A>G		5_prime_UTR_variant, NMD_transcript_variant	1/18	5

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 678 AN: 152214 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0473

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00643 AC: 1010 AN: 157050 Hom.: 23 AF XY: 0.00589 AC XY: 496 AN XY: 84236

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.000242

Gnomad ASJ exome AF: 0.000594

Gnomad EAS exome AF: 0.0408

Gnomad SAS exome AF: 0.00143

Gnomad FIN exome AF: 0.0293

Gnomad NFE exome AF: 0.000504

Gnomad OTH exome AF: 0.00227

GnomAD4 exome AF: 0.00284 AC: 3971 AN: 1398154 Hom.: 83 Cov.: 29 AF XY: 0.00285 AC XY: 1965 AN XY: 690134

Gnomad4 AFR exome AF: 0.0000314

Gnomad4 AMR exome AF: 0.000195

Gnomad4 ASJ exome AF: 0.000756

Gnomad4 EAS exome AF: 0.0512

Gnomad4 SAS exome AF: 0.00186

Gnomad4 FIN exome AF: 0.0302

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.00278

GnomAD4 genome AF: 0.00445 AC: 678 AN: 152332 Hom.: 8 Cov.: 33 AF XY: 0.00568 AC XY: 423 AN XY: 74496

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0474

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00199

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 04, 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. -

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

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	2.9
Dann	Benign	0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2

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: rs28372853; hg19: chr3-158362393;