10-1000765-G-A

Variant names:

• chr10-1000765-G-A
• rs150247999
• NM_012341.3:c.743G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56
• Publications: 4 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40839213).
• BS2: High AC in GnomAd4 at 153 AD gene.

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.743G>A	p.Arg248His	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.743G>A	p.Arg248His	missense	Exon 7 of 17	ENSP00000354040.4	Q9BZE4-1
	GTPBP4	ENST00000925422.1		c.779G>A	p.Arg260His	missense	Exon 8 of 18	ENSP00000595481.1
	GTPBP4	ENST00000925423.1		c.743G>A	p.Arg248His	missense	Exon 7 of 17	ENSP00000595482.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 151978 Hom.: 0 Cov.: 29

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

GnomAD2 exomes AF: 0.000633 AC: 156 AN: 246278 AF XY: 0.000639

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 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.: 3 Cov.: 30 AF XY: 0.00145 AC XY: 1047 AN XY: 723890

African (AFR) AF: 0.000150 AC: 5 AN: 33366

American (AMR) AF: 0.000476 AC: 21 AN: 44116

Ashkenazi Jewish (ASJ) AF: 0.000660 AC: 17 AN: 25764

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39612

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85166

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53234

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5734

European-Non Finnish (NFE) AF: 0.00183 AC: 2033 AN: 1108924

Other (OTH) AF: 0.00180 AC: 108 AN: 60162

GnomAD4 genome AF: 0.00101 AC: 153 AN: 152096 Hom.: 0 Cov.: 29 AF XY: 0.000968 AC XY: 72 AN XY: 74348

African (AFR) AF: 0.000482 AC: 20 AN: 41472

American (AMR) AF: 0.000524 AC: 8 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00174 AC: 118 AN: 68000

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00106

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.000601 AC: 73

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.41
Sift	Benign	0.064	T
Sift4G	Benign	0.10	T
Polyphen		0.93	P
Vest4		0.80
MVP		0.57
MPC		0.34
ClinPred		0.15	T
GERP RS		6.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.21
gMVP		0.75
Mutation Taster		=45/55	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: rs150247999; hg19: chr10-1046705; COSMIC: COSV104416281; COSMIC: COSV104416281;