rs139397531

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_032380.5(GFM2):c.2210T>C(p.Met737Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000434 in 1,612,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GFM2
NM_032380.5 missense, splice_region

Scores

Splicing: ADA: 0.02521

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.02

Publications

0 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: Genomics England PanelApp, Myriad Women’s Health, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

HEXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.779

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032380.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFM2	NM_032380.5	MANE Select	c.2210T>C	p.Met737Thr	missense splice_region	Exon 20 of 21	NP_115756.2
GFM2	NM_001281302.2		c.2306T>C	p.Met769Thr	missense splice_region	Exon 21 of 22	NP_001268231.1
GFM2	NM_170691.3		c.2069T>C	p.Met690Thr	missense splice_region	Exon 19 of 20	NP_733792.1	Q969S9-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFM2	ENST00000296805.8	TSL:1 MANE Select	c.2210T>C	p.Met737Thr	missense splice_region	Exon 20 of 21	ENSP00000296805.3	Q969S9-1
GFM2	ENST00000509430.5	TSL:1	c.2210T>C	p.Met737Thr	missense splice_region	Exon 21 of 22	ENSP00000427004.1	Q969S9-1
GFM2	ENST00000345239.6	TSL:1	c.2069T>C	p.Met690Thr	missense splice_region	Exon 19 of 20	ENSP00000296804.3	Q969S9-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000799

AC:

AN:

250374

AF XY:

0.00000739

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460572

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726634

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33448

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26114

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53036

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111302

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0000723

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.052

MetaRNN

Pathogenic

0.78

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.4

PhyloP100

7.0

PrimateAI

Uncertain

0.67

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.26

Sift

Benign

0.21

Sift4G

Benign

0.53

Polyphen

0.41

Vest4

0.88

MVP

0.71

MPC

0.68

ClinPred

0.84

GERP RS

3.5

Varity_R

0.46

gMVP

0.80

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.025

dbscSNV1_RF

Benign

0.17

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over