rs13440581

Variant names:

• chrX-151181399-A-G
• rs13440581
• NM_004224.3:c.1816A>G

Variant summary

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

The NM_004224.3(GPR50):​c.1816A>G​(p.Ile606Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 110,801 control chromosomes in the GnomAD database, including 9,053 homozygotes. There are 14,558 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 (9053 hom., 14558 hem., cov: 23)
  • Exomes 𝑓: 0.55 (115734 hom. 190785 hem.)
  • Failed GnomAD Quality Control
• Consequence: GPR50 NM_004224.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16

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=2.012317E-5).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.577 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR50	NM_004224.3	c.1816A>G	p.Ile606Val	missense_variant	Exon 2 of 2	ENST00000218316.4	NP_004215.2
GPR50	XM_011531216.3	c.1075A>G	p.Ile359Val	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.1816A>G	p.Ile606Val	missense_variant	Exon 2 of 2	1	NM_004224.3	ENSP00000218316.3

Frequencies

GnomAD3 genomes AF: 0.450 AC: 49878 AN: 110747 Hom.: 9057 Cov.: 23 AF XY: 0.441 AC XY: 14543 AN XY: 32993

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.608

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.590

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.582

Gnomad OTH AF: 0.457

GnomAD3 exomes AF: 0.449 AC: 75716 AN: 168779 Hom.: 12893 AF XY: 0.465 AC XY: 26591 AN XY: 57189

Gnomad AFR exome AF: 0.265

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.590

Gnomad EAS exome AF: 0.0101

Gnomad SAS exome AF: 0.356

Gnomad FIN exome AF: 0.608

Gnomad NFE exome AF: 0.587

Gnomad OTH exome AF: 0.489

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.547 AC: 590474 AN: 1080144 Hom.: 115734 Cov.: 30 AF XY: 0.545 AC XY: 190785 AN XY: 350376

Gnomad4 AFR exome AF: 0.273

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.604

Gnomad4 EAS exome AF: 0.00697

Gnomad4 SAS exome AF: 0.368

Gnomad4 FIN exome AF: 0.604

Gnomad4 NFE exome AF: 0.595

Gnomad4 OTH exome AF: 0.508

GnomAD4 genome AF: 0.450 AC: 49879 AN: 110801 Hom.: 9053 Cov.: 23 AF XY: 0.440 AC XY: 14558 AN XY: 33057

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.358

Gnomad4 ASJ AF: 0.608

Gnomad4 EAS AF: 0.0138

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.590

Gnomad4 NFE AF: 0.582

Gnomad4 OTH AF: 0.452

Alfa AF: 0.540 Hom.: 38476

Bravo AF: 0.421

TwinsUK AF: 0.605 AC: 2244

ALSPAC AF: 0.595 AC: 1718

ESP6500AA AF: 0.271 AC: 996

ESP6500EA AF: 0.583 AC: 3870

ExAC AF: 0.455 AC: 55079

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.11
DANN	Benign	0.60
DEOGEN2	Benign	0.058	T
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.000020	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.070	N
REVEL	Benign	0.069
Sift	Benign	0.22	T
Sift4G	Uncertain	0.022	D
Polyphen		0.010	B
Vest4		0.062
MPC		0.12
ClinPred		0.011	T
GERP RS		2.1
Varity_R		0.058
gMVP		0.055

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: rs13440581; hg19: chrX-150349871; COSMIC: COSV54438870; COSMIC: COSV54438870;