1-6249729-G-A

Variant names:

• chr1-6249729-G-A
• rs1050565050
• NM_207370.4:c.1439C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_207370.4(GPR153):​c.1439C>T​(p.Pro480Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000497 in 1,054,578 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P480S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00068 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (8 hom.)
• Consequence: GPR153 NM_207370.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.636
• Publications: 2 publications found

Genes affected

GPR153 (HGNC:23618): (G protein-coupled receptor 153) This gene encodes an integral membrane protein that belongs to the Class A rhodopsin superfamily of G protein coupled receptors. The encoded protein is expressed primarily in the central nervous system. A knockdown of the orthologous gene in rat is associated with a significant reduction in food intake and impaired decision making ability. Mutations in this gene are associated with schizophrenia, autism, and other neuropsychiatric disorders. The expression of this gene is activated by the glioma-associated oncogene homolog 1 transcription factor which, in turn, is activated by sonic hedgehog in normal and tumorigenic cells. [provided by RefSeq, Feb 2017]

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051596463).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000468 (424/906940) while in subpopulation SAS AF = 0.0183 (329/17986). AF 95% confidence interval is 0.0167. There are 8 homozygotes in GnomAdExome4. There are 217 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207370.4. 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
	GPR153	NM_207370.4	MANE Select	c.1439C>T	p.Pro480Leu	missense	Exon 6 of 6	NP_997253.2	A0A0I9QQ03

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR153	ENST00000377893.3	TSL:1 MANE Select	c.1439C>T	p.Pro480Leu	missense	Exon 6 of 6	ENSP00000367125.2	Q6NV75
	GPR153	ENST00000937750.1		c.1466C>T	p.Pro489Leu	missense	Exon 6 of 6	ENSP00000607809.1
	GPR153	ENST00000937749.1		c.1439C>T	p.Pro480Leu	missense	Exon 6 of 6	ENSP00000607808.1

Frequencies

GnomAD3 genomes AF: 0.000678 AC: 100 AN: 147532 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000673

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.0151

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.0000604

Gnomad OTH AF: 0.000981

GnomAD2 exomes AF: 0.00 AC: 0 AN: 152 AF XY: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000468 AC: 424 AN: 906940 Hom.: 8 Cov.: 31 AF XY: 0.000511 AC XY: 217 AN XY: 424792

African (AFR) AF: 0.000230 AC: 4 AN: 17384

American (AMR) AF: 0.00 AC: 0 AN: 3370

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7242

East Asian (EAS) AF: 0.000121 AC: 1 AN: 8232

South Asian (SAS) AF: 0.0183 AC: 329 AN: 17986

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8484

Middle Eastern (MID) AF: 0.00400 AC: 8 AN: 1998

European-Non Finnish (NFE) AF: 0.0000506 AC: 41 AN: 810560

Other (OTH) AF: 0.00129 AC: 41 AN: 31684

GnomAD4 genome AF: 0.000677 AC: 100 AN: 147638 Hom.: 3 Cov.: 32 AF XY: 0.000973 AC XY: 70 AN XY: 71970

African (AFR) AF: 0.000438 AC: 18 AN: 41052

American (AMR) AF: 0.0000672 AC: 1 AN: 14874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5104

South Asian (SAS) AF: 0.0151 AC: 73 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8878

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.0000604 AC: 4 AN: 66254

Other (OTH) AF: 0.000971 AC: 2 AN: 2060

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000215

ClinVar

ClinVar submissions as Germline

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	0.089
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.92
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N
PhyloP100		0.64
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.024
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.092
MVP		0.24
MPC		0.45
ClinPred		0.099	T
GERP RS		1.5
Varity_R		0.066
gMVP		0.33
Mutation Taster		=93/7	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: rs1050565050; hg19: chr1-6309789;