13-26759533-T-A

Variant names:

• chr13-26759533-T-A
• rs760020683
• NM_005288.4:c.295A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005288.4(GPR12):​c.295A>T​(p.Thr99Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: GPR12 NM_005288.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

Genes affected

GPR12 (HGNC:4466): (G protein-coupled receptor 12) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway and regulation of metabolic process. Predicted to act upstream of or within G protein-coupled receptor signaling pathway and cellular calcium ion homeostasis. Predicted to be integral component of plasma membrane. Predicted to be active in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10246453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR12	NM_005288.4	c.295A>T	p.Thr99Ser	missense_variant	Exon 2 of 2	ENST00000405846.5	NP_005279.1
GPR12	XM_005266360.3	c.-88-95A>T		intron_variant	Intron 1 of 1		XP_005266417.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR12	ENST00000405846.5	c.295A>T	p.Thr99Ser	missense_variant	Exon 2 of 2	1	NM_005288.4	ENSP00000384932.3
GPR12	ENST00000381436.2	c.295A>T	p.Thr99Ser	missense_variant	Exon 1 of 1	6		ENSP00000370844.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251402 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.295A>T (p.T99S) alteration is located in exon 2 (coding exon 1) of the GPR12 gene. This alteration results from a A to T substitution at nucleotide position 295, causing the threonine (T) at amino acid position 99 to be replaced by a serine (S). 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	0.12
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.085	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.67	.;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;B
Vest4		0.031
MutPred		0.56		Gain of catalytic residue at N100 (P = 8e-04);Gain of catalytic residue at N100 (P = 8e-04);
MVP		0.42
MPC		0.70
ClinPred		0.19	T
GERP RS		-3.1
Varity_R		0.23
gMVP		0.23

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

LitVar

Other links and lift over

dbSNP: rs760020683; hg19: chr13-27333670;