5-74721765-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 9.60

Publications

19 publications found

Variant links:

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 links:

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]

HEXB Gene-Disease associations (from GenCC):

Sandhoff disease
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen, Genomics England PanelApp, Myriad Women’s Health

HEXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFM2	NM_032380.5 link	c.2230C>G	p.Arg744Gly	missense_variant	Exon 21 of 21	ENST00000296805.8	NP_115756.2	Q969S9-1A0A024RAK1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFM2	ENST00000296805.8 link	c.2230C>G	p.Arg744Gly	missense_variant	Exon 21 of 21	1	NM_032380.5	ENSP00000296805.3		Q969S9-1

Frequencies

GnomAD3 genomes

AF:

0.0146

AC:

2219

AN:

152102

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0166

AC:

4140

AN:

249612

AF XY:

0.0160

show subpopulations

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 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.:

AF XY:

0.0176

AC XY:

12773

AN XY:

726300

show subpopulations

African (AFR)

AF:

0.00619

AC:

207

AN:

33418

American (AMR)

AF:

0.0275

AC:

1221

AN:

44428

Ashkenazi Jewish (ASJ)

AF:

0.0116

AC:

303

AN:

26096

East Asian (EAS)

AF:

0.0233

AC:

925

AN:

39664

South Asian (SAS)

AF:

0.00885

AC:

760

AN:

85866

European-Finnish (FIN)

AF:

0.00802

AC:

428

AN:

53394

Middle Eastern (MID)

AF:

0.0123

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.0190

AC:

21065

AN:

1111070

Other (OTH)

AF:

0.0171

AC:

1035

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

1103

2206

3310

4413

5516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0146

AC:

2222

AN:

152220

Hom.:

Cov.:

AF XY:

0.0138

AC XY:

1024

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.00715

AC:

297

AN:

41532

American (AMR)

AF:

0.0216

AC:

330

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0150

AC:

AN:

3472

East Asian (EAS)

AF:

0.0187

AC:

AN:

5176

South Asian (SAS)

AF:

0.0125

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00745

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0188

AC:

1276

AN:

68018

Other (OTH)

AF:

0.0104

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

122

244

365

487

609

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0179

Hom.:

Bravo

AF:

0.0155

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0192

AC:

ESP6500AA

AF:

0.00726

AC:

ESP6500EA

AF:

0.0194

AC:

167

ExAC

AF:

0.0165

AC:

2002

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0191

EpiControl

AF:

0.0193

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Dec 09, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jul 23, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;.;T

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

.;D;D

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

4.6

H;.;H

PhyloP100

9.6

PrimateAI

Uncertain

0.60

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

GERP RS

5.8

Varity_R

0.97

gMVP

0.93

Mutation Taster

=88/12

polymorphism (auto)

(source)

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

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5-74721765-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over