5-74721674-C-T

Variant names:

• chr5-74721674-C-T
• rs1048167
• NM_032380.5:c.2321G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 16/21 in silico tools predict 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. R774W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (1886 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11823 hom.)
• Consequence: GFM2 NM_032380.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.558
• Publications: 37 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]

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

ACMG classification

Our verdict: Benign. The variant received -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	c.2321G>A	p.Arg774Gln	missense_variant	Exon 21 of 21	ENST00000296805.8	NP_115756.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFM2	ENST00000296805.8	c.2321G>A	p.Arg774Gln	missense_variant	Exon 21 of 21	1	NM_032380.5	ENSP00000296805.3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22348 AN: 151996 Hom.: 1884 Cov.: 32

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

GnomAD2 exomes AF: 0.117 AC: 29321 AN: 249592 AF XY: 0.119

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 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.: 32 AF XY: 0.123 AC XY: 89001 AN XY: 726098

African (AFR) AF: 0.237 AC: 7915 AN: 33370

American (AMR) AF: 0.0919 AC: 4076 AN: 44370

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 4429 AN: 26084

East Asian (EAS) AF: 0.0158 AC: 627 AN: 39666

South Asian (SAS) AF: 0.108 AC: 9268 AN: 85654

European-Finnish (FIN) AF: 0.115 AC: 6164 AN: 53398

Middle Eastern (MID) AF: 0.210 AC: 1206 AN: 5754

European-Non Finnish (NFE) AF: 0.124 AC: 137448 AN: 1111222

Other (OTH) AF: 0.131 AC: 7876 AN: 60322

GnomAD4 genome AF: 0.147 AC: 22365 AN: 152116 Hom.: 1886 Cov.: 32 AF XY: 0.146 AC XY: 10825 AN XY: 74354

African (AFR) AF: 0.227 AC: 9406 AN: 41486

American (AMR) AF: 0.120 AC: 1829 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3470

East Asian (EAS) AF: 0.0218 AC: 113 AN: 5188

South Asian (SAS) AF: 0.102 AC: 493 AN: 4816

European-Finnish (FIN) AF: 0.106 AC: 1123 AN: 10578

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8377 AN: 67984

Other (OTH) AF: 0.159 AC: 335 AN: 2108

Alfa AF: 0.135 Hom.: 4969

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

Submissions by phenotype

not provided Benign:2

Feb 03, 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

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	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.0047	T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.86	.;D;D
MetaRNN	Benign	0.00084	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.83	L;.;L
PhyloP100		-0.56
PrimateAI	Benign	0.19	T
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	T
GERP RS		-3.3
Varity_R		0.043
gMVP		0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1048167; hg19: chr5-74017499; COSMIC: COSV99714087; COSMIC: COSV99714087;