X-151176899-C-T

Variant names:

• chrX-151176899-C-T
• rs372854533
• NM_004224.3:c.178C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong 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, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.35
• 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: Benign. The variant received -11 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 VariationId is 1206241.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 4 gene

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.178C>T	p.Arg60Trp	missense	Exon 1 of 2	NP_004215.2	Q13585
	GPR50-AS1	NR_135300.1		n.461-24G>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.178C>T	p.Arg60Trp	missense	Exon 1 of 2	ENSP00000218316.3	Q13585
	GPR50-AS1	ENST00000454196.1	TSL:2	n.461-24G>A		intron	N/A
	GPR50-AS1	ENST00000835194.1		n.440+478G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 22 AN: 111452 Hom.: 0 Cov.: 22

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

GnomAD2 exomes AF: 0.000301 AC: 52 AN: 172622 AF XY: 0.000321

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26130

American (AMR) AF: 0.0000863 AC: 3 AN: 34769

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19043

East Asian (EAS) AF: 0.00 AC: 0 AN: 30020

South Asian (SAS) AF: 0.0000378 AC: 2 AN: 52884

European-Finnish (FIN) AF: 0.000693 AC: 28 AN: 40432

Middle Eastern (MID) AF: 0.000247 AC: 1 AN: 4052

European-Non Finnish (NFE) AF: 0.000491 AC: 409 AN: 832625

Other (OTH) AF: 0.000241 AC: 11 AN: 45627

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

African (AFR) AF: 0.000131 AC: 4 AN: 30547

American (AMR) AF: 0.00 AC: 0 AN: 10646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2649

East Asian (EAS) AF: 0.00 AC: 0 AN: 3536

South Asian (SAS) AF: 0.00 AC: 0 AN: 2598

European-Finnish (FIN) AF: 0.000833 AC: 5 AN: 6006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.000226 AC: 12 AN: 53045

Other (OTH) AF: 0.000668 AC: 1 AN: 1498

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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.4
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
PromoterAI		-0.068	Neutral
Varity_R		0.44
gMVP		0.89
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs372854533; hg19: chrX-150345371; COSMIC: COSV54441636;