Variant 10-1000765-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_012341.3(GTPBP4):c.743G>A(p.Arg248His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,608,174 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0015 ( 3 hom. )

Consequence

GTPBP4
NM_012341.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.56

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.40839213).

BS2

High AC in GnomAd4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTPBP4	NM_012341.3 linkuse as main transcript	c.743G>A	p.Arg248His	missense_variant	7/17	ENST00000360803.9
GTPBP4	XM_047424932.1 linkuse as main transcript	c.602G>A	p.Arg201His	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTPBP4	ENST00000360803.9 linkuse as main transcript	c.743G>A	p.Arg248His	missense_variant	7/17	1	NM_012341.3	P1	Q9BZE4-1
GTPBP4	ENST00000491635.1 linkuse as main transcript	n.1622G>A		non_coding_transcript_exon_variant	5/11	2

Frequencies

GnomAD3 genomes

AF:

0.00101

AC:

153

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00174

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000633

AC:

156

AN:

246278

Hom.:

AF XY:

0.000639

AC XY:

AN XY:

132922

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000325

Gnomad ASJ exome

AF:

0.000413

Gnomad EAS exome

AF:

0.0000547

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00118

Gnomad OTH exome

AF:

0.000669

GnomAD4 exome

AF:

0.00150

AC:

2188

AN:

1456078

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

1047

AN XY:

723890

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000476

Gnomad4 ASJ exome

AF:

0.000660

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.00183

Gnomad4 OTH exome

AF:

0.00180

GnomAD4 genome

AF:

0.00101

AC:

153

AN:

152096

Hom.:

Cov.:

AF XY:

0.000968

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.000482

Gnomad4 AMR

AF:

0.000524

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00174

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00106

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.000601

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2021

The c.743G>A (p.R248H) alteration is located in exon 7 (coding exon 7) of the GTPBP4 gene. This alteration results from a G to A substitution at nucleotide position 743, causing the arginine (R) at amino acid position 248 to be replaced by a histidine (H). 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

Uncertain

0.42

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.14

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.019

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.8

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.41

Sift

Benign

0.064

Sift4G

Benign

0.10

Polyphen

0.93

Vest4

0.80

MVP

0.57

MPC

0.34

ClinPred

0.15

GERP RS

6.1

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.1

Varity_R

0.21

gMVP

0.75

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