10-997241-A-T

Position:

• chr10-997241-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012341.3(GTPBP4):​c.494A>T​(p.Asp165Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: GTPBP4 NM_012341.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.00

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GTPBP4	NM_012341.3	c.494A>T	p.Asp165Val	missense_variant	5/17	ENST00000360803.9	NP_036473.2
GTPBP4	XM_047424932.1	c.353A>T	p.Asp118Val	missense_variant	5/17		XP_047280888.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GTPBP4	ENST00000360803.9	c.494A>T	p.Asp165Val	missense_variant	5/17	1	NM_012341.3	ENSP00000354040.4
GTPBP4	ENST00000360059.5	c.353A>T	p.Asp118Val	missense_variant	5/5	5		ENSP00000353168.5
GTPBP4	ENST00000491635.1	n.1373A>T		non_coding_transcript_exon_variant	3/11	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 09, 2024

The c.494A>T (p.D165V) alteration is located in exon 5 (coding exon 5) of the GTPBP4 gene. This alteration results from a A to T substitution at nucleotide position 494, causing the aspartic acid (D) at amino acid position 165 to be replaced by a valine (V). 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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-8.5	D;D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.037	D;D
Polyphen		0.86	P;.
Vest4		0.94
MutPred		0.72		Loss of disorder (P = 0.04);.;
MVP		0.71
MPC		0.17
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-1043181; COSMIC: COSV62550091;