5-74721765-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032380.5(GFM2):c.2230C>G(p.Arg744Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,612,260 control chromosomes in the GnomAD database, including 273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R744Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (13 hom., cov: 32)
  • Exomes 𝑓: 0.018 (260 hom.)
• Consequence: GFM2 NM_032380.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.60

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]

HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.011408657).
• BP6: Variant 5-74721765-G-C is Benign according to our data. Variant chr5-74721765-G-C is described in ClinVar as [Benign]. Clinvar id is 137479.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0146 (2222/152220) while in subpopulation AMR AF= 0.0216 (330/15288). AF 95% confidence interval is 0.0197. There are 13 homozygotes in gnomad4. There are 1024 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFM2	NM_032380.5	c.2230C>G	p.Arg744Gly	missense_variant	21/21	ENST00000296805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFM2	ENST00000296805.8	c.2230C>G	p.Arg744Gly	missense_variant	21/21	1	NM_032380.5	P1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2219 AN: 152102 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0189

Gnomad SAS AF: 0.0125

Gnomad FIN AF: 0.00745

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0166 AC: 4140 AN: 249612 Hom.: 40 AF XY: 0.0160 AC XY: 2155 AN XY: 134846

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.0186

Gnomad SAS exome AF: 0.00862

Gnomad FIN exome AF: 0.00768

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0154

GnomAD4 exome AF: 0.0178 AC: 26015 AN: 1460040 Hom.: 260 Cov.: 30 AF XY: 0.0176 AC XY: 12773 AN XY: 726300

Gnomad4 AFR exome AF: 0.00619

Gnomad4 AMR exome AF: 0.0275

Gnomad4 ASJ exome AF: 0.0116

Gnomad4 EAS exome AF: 0.0233

Gnomad4 SAS exome AF: 0.00885

Gnomad4 FIN exome AF: 0.00802

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0171

GnomAD4 genome AF: 0.0146 AC: 2222 AN: 152220 Hom.: 13 Cov.: 32 AF XY: 0.0138 AC XY: 1024 AN XY: 74416

Gnomad4 AFR AF: 0.00715

Gnomad4 AMR AF: 0.0216

Gnomad4 ASJ AF: 0.0150

Gnomad4 EAS AF: 0.0187

Gnomad4 SAS AF: 0.0125

Gnomad4 FIN AF: 0.00745

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0179 Hom.: 21

Bravo AF: 0.0155

TwinsUK AF: 0.0183 AC: 68

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00726 AC: 32

ESP6500EA AF: 0.0194 AC: 167

ExAC AF: 0.0165 AC: 2002

Asia WGS AF: 0.0170 AC: 59 AN: 3478

EpiCase AF: 0.0191

EpiControl AF: 0.0193

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 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. -

GFM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	4.6	H;.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-6.8	D;D;D
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.46
MPC		0.76
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35080306; hg19: chr5-74017590;