rs561077

Variant names:

• chrX-151181177-A-G
• rs561077
• NM_004224.3:c.1594A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004224.3(GPR50):​c.1594A>G​(p.Thr532Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 1,206,901 control chromosomes in the GnomAD database, including 75,857 homozygotes. There are 166,171 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.45 (8070 hom., 13638 hem., cov: 21)
  • Exomes 𝑓: 0.42 (67787 hom. 152533 hem.)
• Consequence: GPR50 NM_004224.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.00

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.339485E-5).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR50	NM_004224.3	c.1594A>G	p.Thr532Ala	missense_variant	Exon 2 of 2	ENST00000218316.4	NP_004215.2
GPR50	XM_011531216.3	c.853A>G	p.Thr285Ala	missense_variant	Exon 2 of 2		XP_011529518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR50	ENST00000218316.4	c.1594A>G	p.Thr532Ala	missense_variant	Exon 2 of 2	1	NM_004224.3	ENSP00000218316.3

Frequencies

GnomAD3 genomes AF: 0.446 AC: 48658 AN: 109013 Hom.: 8073 Cov.: 21 AF XY: 0.433 AC XY: 13594 AN XY: 31377

Gnomad AFR AF: 0.507

Gnomad AMI AF: 0.472

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.250

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.397

Gnomad NFE AF: 0.421

Gnomad OTH AF: 0.461

GnomAD3 exomes AF: 0.430 AC: 78100 AN: 181776 Hom.: 11326 AF XY: 0.417 AC XY: 28066 AN XY: 67340

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.399

Gnomad EAS exome AF: 0.256

Gnomad SAS exome AF: 0.372

Gnomad FIN exome AF: 0.445

Gnomad NFE exome AF: 0.423

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.425 AC: 466240 AN: 1097831 Hom.: 67787 Cov.: 39 AF XY: 0.420 AC XY: 152533 AN XY: 363257

Gnomad4 AFR exome AF: 0.513

Gnomad4 AMR exome AF: 0.532

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.369

Gnomad4 FIN exome AF: 0.441

Gnomad4 NFE exome AF: 0.427

Gnomad4 OTH exome AF: 0.436

GnomAD4 genome AF: 0.446 AC: 48699 AN: 109070 Hom.: 8070 Cov.: 21 AF XY: 0.434 AC XY: 13638 AN XY: 31444

Gnomad4 AFR AF: 0.508

Gnomad4 AMR AF: 0.512

Gnomad4 ASJ AF: 0.389

Gnomad4 EAS AF: 0.250

Gnomad4 SAS AF: 0.338

Gnomad4 FIN AF: 0.427

Gnomad4 NFE AF: 0.421

Gnomad4 OTH AF: 0.460

Alfa AF: 0.422 Hom.: 31009

Bravo AF: 0.457

TwinsUK AF: 0.410 AC: 1520

ALSPAC AF: 0.427 AC: 1235

ESP6500AA AF: 0.499 AC: 1892

ESP6500EA AF: 0.416 AC: 2782

ExAC AF: 0.421 AC: 51034

EpiCase AF: 0.426

EpiControl AF: 0.419

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.0060
DANN	Benign	0.31
DEOGEN2	Benign	0.043	T
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.000053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.076
Sift	Benign	0.55	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.14
ClinPred		0.0091	T
GERP RS		-3.2
Varity_R		0.027
gMVP		0.096

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: rs561077; hg19: chrX-150349649; COSMIC: COSV54437075; COSMIC: COSV54437075;