5-74721674-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_032380.5(GFM2):c.2321G>A(p.Arg774Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.125 in 1,611,956 control chromosomes in the GnomAD database, including 13,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 1886 hom., cov: 32)

Exomes 𝑓: 0.12 ( 11823 hom. )

Consequence

GFM2
NM_032380.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.558

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.44121E-4).

BP6

Variant 5-74721674-C-T is Benign according to our data. Variant chr5-74721674-C-T is described in ClinVar as [Benign]. Clinvar id is 137480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFM2	NM_032380.5 link	c.2321G>A	p.Arg774Gln	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.2321G>A	p.Arg774Gln	missense_variant	Exon 21 of 21	1	NM_032380.5	ENSP00000296805.3		Q969S9-1

Frequencies

GnomAD3 genomes

AF:

0.147

AC:

22348

AN:

151996

Hom.:

1884

Cov.:

show subpopulations

Gnomad AFR

AF:

0.227

Gnomad AMI

AF:

0.0943

Gnomad AMR

AF:

0.120

Gnomad ASJ

AF:

0.158

Gnomad EAS

AF:

0.0217

Gnomad SAS

AF:

0.102

Gnomad FIN

AF:

0.106

Gnomad MID

AF:

0.194

Gnomad NFE

AF:

0.123

Gnomad OTH

AF:

0.162

GnomAD3 exomes

AF:

0.117

AC:

29321

AN:

249592

Hom.:

2050

AF XY:

0.119

AC XY:

16006

AN XY:

134758

show subpopulations

Gnomad AFR exome

AF:

0.224

Gnomad AMR exome

AF:

0.0885

Gnomad ASJ exome

AF:

0.172

Gnomad EAS exome

AF:

0.0231

Gnomad SAS exome

AF:

0.106

Gnomad FIN exome

AF:

0.113

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.123

AC:

179009

AN:

1459840

Hom.:

11823

Cov.:

AF XY:

0.123

AC XY:

89001

AN XY:

726098

show subpopulations

Gnomad4 AFR exome

AF:

0.237

Gnomad4 AMR exome

AF:

0.0919

Gnomad4 ASJ exome

AF:

0.170

Gnomad4 EAS exome

AF:

0.0158

Gnomad4 SAS exome

AF:

0.108

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.124

Gnomad4 OTH exome

AF:

0.131

GnomAD4 genome

AF:

0.147

AC:

22365

AN:

152116

Hom.:

1886

Cov.:

AF XY:

0.146

AC XY:

10825

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.227

Gnomad4 AMR

AF:

0.120

Gnomad4 ASJ

AF:

0.158

Gnomad4 EAS

AF:

0.0218

Gnomad4 SAS

AF:

0.102

Gnomad4 FIN

AF:

0.106

Gnomad4 NFE

AF:

0.123

Gnomad4 OTH

AF:

0.159

Alfa

AF:

0.135

Hom.:

2497

Bravo

AF:

0.153

TwinsUK

AF:

0.132

AC:

491

ALSPAC

AF:

0.125

AC:

480

ESP6500AA

AF:

0.225

AC:

991

ESP6500EA

AF:

0.124

AC:

1066

ExAC

AF:

0.120

AC:

14568

Asia WGS

AF:

0.0740

AC:

258

AN:

3478

EpiCase

AF:

0.133

EpiControl

AF:

0.133

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Sep 17, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0047

T;.;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.29

LIST_S2

Uncertain

0.86

.;D;D

MetaRNN

Benign

0.00084

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.83

L;.;L

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.059

Sift

Benign

0.33

T;T;T

Sift4G

Benign

0.23

T;T;T

Polyphen

0.017

B;B;B

Vest4

0.032

MPC

0.18

ClinPred

0.018

GERP RS

-3.3

Varity_R

0.043

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over