12-12661652-A-G

Position:

• chr12-12661652-A-G

Variant summary

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

The NM_006143.3(GPR19):​c.797T>C​(p.Ile266Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,626 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPR19 NM_006143.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

Genes affected

GPR19 (HGNC:4473): (G protein-coupled receptor 19) Predicted to enable G protein-coupled receptor activity. Predicted to be involved in G protein-coupled receptor signaling pathway. Located in cilium. [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=0.17944857).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR19	NM_006143.3	c.797T>C	p.Ile266Thr	missense_variant	4/4	ENST00000651487.1	NP_006134.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR19	ENST00000651487.1	c.797T>C	p.Ile266Thr	missense_variant	4/4		NM_006143.3	ENSP00000498976.1
GPR19	ENST00000332427.6	c.797T>C	p.Ile266Thr	missense_variant	4/4	4		ENSP00000333744.2
GPR19	ENST00000540510.1	c.797T>C	p.Ile266Thr	missense_variant	2/2	2		ENSP00000441832.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461626 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Apr 29, 2024

The c.797T>C (p.I266T) alteration is located in exon 4 (coding exon 1) of the GPR19 gene. This alteration results from a T to C substitution at nucleotide position 797, causing the isoleucine (I) at amino acid position 266 to be replaced by a threonine (T). 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	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.069
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.16
Sift	Benign	1.0	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.21	B;B
Vest4		0.15
MutPred		0.59		Gain of disorder (P = 0.0084);Gain of disorder (P = 0.0084);
MVP		0.55
MPC		0.51
ClinPred		0.81	D
GERP RS		5.6
Varity_R		0.19

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

Other links and lift over

dbSNP: rs1945675956; hg19: chr12-12814586;