5-74721255-CTG-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_032380.5(GFM2):c.*398_*399del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.113 in 1,121,738 control chromosomes in the GnomAD database, including 8,210 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (846 hom., cov: 31)
  • Exomes 𝑓: 0.12 (7364 hom.)
• Consequence: GFM2 NM_032380.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.974

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 5-74721255-CTG-C is Benign according to our data. Variant chr5-74721255-CTG-C is described in ClinVar as [Likely_benign]. Clinvar id is 354140.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXB	NM_000521.4	c.*82_*83del		3_prime_UTR_variant	14/14	ENST00000261416.12
GFM2	NM_032380.5	c.*398_*399del		3_prime_UTR_variant	21/21	ENST00000296805.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXB	ENST00000261416.12	c.*82_*83del		3_prime_UTR_variant	14/14	1	NM_000521.4	P1
GFM2	ENST00000296805.8	c.*398_*399del		3_prime_UTR_variant	21/21	1	NM_032380.5	P1

Frequencies

GnomAD3 genomes AF: 0.0945 AC: 14367 AN: 152056 Hom.: 843 Cov.: 31

Gnomad AFR AF: 0.0219

Gnomad AMI AF: 0.228

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.0819

GnomAD4 exome AF: 0.116 AC: 112855 AN: 969564 Hom.: 7364 AF XY: 0.115 AC XY: 57995 AN XY: 502980

Gnomad4 AFR exome AF: 0.0202

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.158

Gnomad4 SAS exome AF: 0.0772

Gnomad4 FIN exome AF: 0.137

Gnomad4 NFE exome AF: 0.117

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.0945 AC: 14374 AN: 152174 Hom.: 846 Cov.: 31 AF XY: 0.0952 AC XY: 7084 AN XY: 74396

Gnomad4 AFR AF: 0.0218

Gnomad4 AMR AF: 0.113

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.139

Gnomad4 SAS AF: 0.0725

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.123

Gnomad4 OTH AF: 0.0825

Alfa AF: 0.108 Hom.: 98

Bravo AF: 0.0921

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sandhoff disease Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 16, 2021

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs56312827; hg19: chr5-74017080;