Genetic Variant GTPBP4:p.Thr22Met (chr10-992505-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012341.3(GTPBP4):c.65C>T(p.Thr22Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,445,194 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

GTPBP4
NM_012341.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.56

Variant links:

Genes affected

GTPBP4 (HGNC:21535): (GTP binding protein 4) GTP-binding proteins are GTPases and function as molecular switches that can flip between two states: active, when GTP is bound, and inactive, when GDP is bound. 'Active' in this context usually means that the molecule acts as a signal to trigger other events in the cell. When an extracellular ligand binds to a G-protein-linked receptor, the receptor changes its conformation and switches on the trimeric G proteins that associate with it by causing them to eject their GDP and replace it with GTP. The switch is turned off when the G protein hydrolyzes its own bound GTP, converting it back to GDP. But before that occurs, the active protein has an opportunity to diffuse away from the receptor and deliver its message for a prolonged period to its downstream target. [provided by RefSeq, Jul 2008]

GTPBP4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GTPBP4	NM_012341.3 link	c.65C>T	p.Thr22Met	missense_variant	Exon 2 of 17	ENST00000360803.9	NP_036473.2	Q9BZE4-1D2CFK9
GTPBP4	XM_047424932.1 link	c.-77C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 17		XP_047280888.1
GTPBP4	XM_047424932.1 link	c.-77C>T		5_prime_UTR_variant	Exon 2 of 17		XP_047280888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GTPBP4	ENST00000360803.9 link	c.65C>T	p.Thr22Met	missense_variant	Exon 2 of 17	1	NM_012341.3	ENSP00000354040.4	Q9BZE4-1
GTPBP4	ENST00000360059 link	c.-77C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 5	5		ENSP00000353168.5	Q5T3R7
GTPBP4	ENST00000360059 link	c.-77C>T		5_prime_UTR_variant	Exon 2 of 5	5		ENSP00000353168.5	Q5T3R7
GTPBP4	ENST00000491635.1 link	n.83C>T		non_coding_transcript_exon_variant	Exon 2 of 11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250510

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000692

AC:

AN:

1445194

Hom.:

Cov.:

AF XY:

0.00000833

AC XY:

AN XY:

719964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000729

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.65C>T (p.T22M) alteration is located in exon 2 (coding exon 2) of the GTPBP4 gene. This alteration results from a C to T substitution at nucleotide position 65, causing the threonine (T) at amino acid position 22 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Uncertain

0.010

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.0069

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.0090

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.90

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.29

REVEL

Benign

0.22

Sift

Benign

0.078

Sift4G

Uncertain

0.060

Polyphen

0.23

Vest4

0.80

MutPred

0.45

Gain of helix (P = 0.062);

MVP

0.80

MPC

0.31

ClinPred

0.71

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.095

gMVP

0.79

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