chrX-151176738-C-T

Variant names:

• chrX-151176738-C-T
• rs1157091999
• NM_004224.3:c.17C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004224.3(GPR50):​c.17C>T​(p.Ala6Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000059 in 1,185,940 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 21)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: GPR50 NM_004224.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.952
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2946542).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004224.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR50	NM_004224.3	MANE Select	c.17C>T	p.Ala6Val	missense	Exon 1 of 2	NP_004215.2	Q13585
	GPR50-AS1	NR_135300.1		n.541+57G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR50	ENST00000218316.4	TSL:1 MANE Select	c.17C>T	p.Ala6Val	missense	Exon 1 of 2	ENSP00000218316.3	Q13585
	GPR50-AS1	ENST00000454196.1	TSL:2	n.541+57G>A		intron	N/A
	GPR50-AS1	ENST00000835194.1		n.440+639G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110464 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000379

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000465 AC: 5 AN: 1075476 Hom.: 0 Cov.: 27 AF XY: 0.00000289 AC XY: 1 AN XY: 345702

African (AFR) AF: 0.00 AC: 0 AN: 25606

American (AMR) AF: 0.00 AC: 0 AN: 32786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18328

East Asian (EAS) AF: 0.00 AC: 0 AN: 29539

South Asian (SAS) AF: 0.00 AC: 0 AN: 50615

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40147

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3526

European-Non Finnish (NFE) AF: 0.00000603 AC: 5 AN: 829831

Other (OTH) AF: 0.00 AC: 0 AN: 45098

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110464 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 32718

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30278

American (AMR) AF: 0.00 AC: 0 AN: 10526

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3483

South Asian (SAS) AF: 0.00 AC: 0 AN: 2531

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5920

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.0000379 AC: 2 AN: 52702

Other (OTH) AF: 0.00 AC: 0 AN: 1477

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.070	T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.95
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.24
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.040	D
Polyphen		0.99	D
Vest4		0.17
MutPred		0.50		Loss of disorder (P = 0.1084)
MVP		0.90
MPC		0.15
ClinPred		0.32	T
GERP RS		4.2
PromoterAI		-0.040	Neutral
Varity_R		0.094
gMVP		0.43
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs1157091999; hg19: chrX-150345210;