X-151176899-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP3 BP6_Moderate BS2

The NM_004224.3(GPR50):c.178C>T(p.Arg60Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,197,034 control chromosomes in the GnomAD database, including 1 homozygotes. There are 144 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R60Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 4 hem., cov: 22)
  • Exomes 𝑓: 0.00042 (1 hom. 140 hem.)
• Consequence: GPR50 NM_004224.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 1.35

Genes affected

GPR50 (HGNC:4506): (G protein-coupled receptor 50) This gene product belongs to the G-protein coupled receptor 1 family. Even though this protein shares similarity with the melatonin receptors, it does not bind melatonin, however, it inhibits melatonin receptor 1A function through heterodimerization. Polymorphic variants of this gene have been associated with bipolar affective disorder in women. [provided by RefSeq, Jan 2010]

GPR50-AS1 (HGNC:40259): (GPR50 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.791
• BP6: Variant X-151176899-C-T is Benign according to our data. Variant chrX-151176899-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1206241.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-151176899-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR50	NM_004224.3	c.178C>T	p.Arg60Trp	missense_variant	1/2	ENST00000218316.4
GPR50-AS1	NR_135300.1	n.461-24G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR50	ENST00000218316.4	c.178C>T	p.Arg60Trp	missense_variant	1/2	1	NM_004224.3	P1
GPR50-AS1	ENST00000454196.1	n.461-24G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111452 Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4 AN XY: 33632

Gnomad AFR AF: 0.000131

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: 0.000833

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000226

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.000301 AC: 52 AN: 172622 Hom.: 0 AF XY: 0.000321 AC XY: 19 AN XY: 59128

Gnomad AFR exome AF: 0.0000820

Gnomad AMR exome AF: 0.0000765

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000764

Gnomad NFE exome AF: 0.000476

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000418 AC: 454 AN: 1085582 Hom.: 1 Cov.: 27 AF XY: 0.000398 AC XY: 140 AN XY: 351700

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000863

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000378

Gnomad4 FIN exome AF: 0.000693

Gnomad4 NFE exome AF: 0.000491

Gnomad4 OTH exome AF: 0.000241

GnomAD4 genome AF: 0.000197 AC: 22 AN: 111452 Hom.: 0 Cov.: 22 AF XY: 0.000119 AC XY: 4 AN XY: 33632

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000833

Gnomad4 NFE AF: 0.000226

Gnomad4 OTH AF: 0.000668

Alfa AF: 0.000216 Hom.: 0

Bravo AF: 0.000144

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000311 AC: 2

ExAC AF: 0.000331 AC: 40

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	GPR50: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.0079	T
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Pathogenic	4.1	H
MutationTaster	Benign	0.51	N
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.89
MPC		0.40
ClinPred		0.46	T
GERP RS		4.4
Varity_R		0.44
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs372854533; hg19: chrX-150345371; COSMIC: COSV54441636;