rs140077535

Variant names:

• chr5-74726125-A-T
• rs140077535
• NM_032380.5:c.1728T>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_032380.5(GFM2):​c.1728T>A​(p.Asp576Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000202 in 1,595,268 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00098 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (1 hom.)
• Consequence: GFM2 NM_032380.5 missense, splice_region
• Scores: Splicing: ADA: 0.0007140
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:1
• Conservation: PhyloP100: 2.73
• Publications: 4 publications found

Genes affected

GFM2 (HGNC:29682): (GTP dependent ribosome recycling factor mitochondrial 2) 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, which is a GTPase that plays a role at the termination of mitochondrial translation by mediating the disassembly of ribosomes from messenger RNA . Its role in the regulation of normal mitochondrial function and in disease states attributed to mitochondrial dysfunction is not known. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2013]

GFM2 Gene-Disease associations (from GenCC):

• combined oxidative phosphorylation deficiency 39

  Inheritance: AR Classification: MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010352671).
• BP6: Variant 5-74726125-A-T is Benign according to our data. Variant chr5-74726125-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 55856.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000985 (150/152352) while in subpopulation AFR AF = 0.00329 (137/41588). AF 95% confidence interval is 0.00285. There are 1 homozygotes in GnomAd4. There are 66 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032380.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM2	NM_032380.5	MANE Select	c.1728T>A	p.Asp576Glu	missense splice_region	Exon 18 of 21	NP_115756.2
	GFM2	NM_001281302.2		c.1824T>A	p.Asp608Glu	missense splice_region	Exon 19 of 22	NP_001268231.1
	GFM2	NM_170691.3		c.1587T>A	p.Asp529Glu	missense splice_region	Exon 17 of 20	NP_733792.1	Q969S9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFM2	ENST00000296805.8	TSL:1 MANE Select	c.1728T>A	p.Asp576Glu	missense splice_region	Exon 18 of 21	ENSP00000296805.3	Q969S9-1
	GFM2	ENST00000509430.5	TSL:1	c.1728T>A	p.Asp576Glu	missense splice_region	Exon 19 of 22	ENSP00000427004.1	Q969S9-1
	GFM2	ENST00000345239.6	TSL:1	c.1587T>A	p.Asp529Glu	missense splice_region	Exon 17 of 20	ENSP00000296804.3	Q969S9-2

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152234 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000252 AC: 59 AN: 234026 AF XY: 0.000134

Gnomad AFR exome AF: 0.00286

Gnomad AMR exome AF: 0.000393

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000935

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000120 AC: 173 AN: 1442916 Hom.: 1 Cov.: 30 AF XY: 0.0000977 AC XY: 70 AN XY: 716686

African (AFR) AF: 0.00415 AC: 133 AN: 32056

American (AMR) AF: 0.000366 AC: 15 AN: 41000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.0000477 AC: 4 AN: 83806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103710

Other (OTH) AF: 0.000319 AC: 19 AN: 59624

GnomAD4 genome AF: 0.000985 AC: 150 AN: 152352 Hom.: 1 Cov.: 32 AF XY: 0.000886 AC XY: 66 AN XY: 74498

African (AFR) AF: 0.00329 AC: 137 AN: 41588

American (AMR) AF: 0.000719 AC: 11 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000192 Hom.: 0

Bravo AF: 0.00112

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000280 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
1	-	-	Combined oxidative phosphorylation deficiency 39 (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.7
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.15
Sift	Benign	0.27	T
Sift4G	Benign	0.27	T
Polyphen		0.024	B
Vest4		0.58
MutPred		0.41		Gain of solvent accessibility (P = 0.0854)
MVP		0.42
MPC		0.57
ClinPred		0.042	T
GERP RS		1.8
Varity_R		0.17
gMVP		0.56
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00071
dbscSNV1_RF	Benign	0.082
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

Other links and lift over

dbSNP: rs140077535; hg19: chr5-74021950;