10-1000716-G-C

Variant names:

• chr10-1000716-G-C
• rs752471400
• NM_012341.3:c.694G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012341.3(GTPBP4):​c.694G>C​(p.Asp232His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000319 in 1,568,250 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D232Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GTPBP4 NM_012341.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.56
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012341.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTPBP4	NM_012341.3	MANE Select	c.694G>C	p.Asp232His	missense	Exon 7 of 17	NP_036473.2	Q9BZE4-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GTPBP4	ENST00000360803.9	TSL:1 MANE Select	c.694G>C	p.Asp232His	missense	Exon 7 of 17	ENSP00000354040.4	Q9BZE4-1
	GTPBP4	ENST00000925422.1		c.730G>C	p.Asp244His	missense	Exon 8 of 18	ENSP00000595481.1
	GTPBP4	ENST00000925423.1		c.694G>C	p.Asp232His	missense	Exon 7 of 17	ENSP00000595482.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151968 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1416282 Hom.: 0 Cov.: 30 AF XY: 0.00000286 AC XY: 2 AN XY: 700008

African (AFR) AF: 0.00 AC: 0 AN: 32264

American (AMR) AF: 0.00 AC: 0 AN: 38364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22830

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 77384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5548

European-Non Finnish (NFE) AF: 0.00000367 AC: 4 AN: 1090168

Other (OTH) AF: 0.00 AC: 0 AN: 58576

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151968 Hom.: 0 Cov.: 29 AF XY: 0.0000135 AC XY: 1 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41340

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.6
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.96	D
Vest4		0.36
MutPred		0.79		Loss of disorder (P = 0.1386)
MVP		0.38
MPC		0.29
ClinPred		0.97	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.47
gMVP		0.66
Mutation Taster		=48/52	disease causing

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

Other links and lift over

dbSNP: rs752471400; hg19: chr10-1046656;