chr1-6249730-G-A

Variant names:

• chr1-6249730-G-A
• rs889580535
• NM_207370.4:c.1438C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207370.4(GPR153):​c.1438C>T​(p.Pro480Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,055,974 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P480L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: GPR153 NM_207370.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.920
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05332297).

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.1438C>T	p.Pro480Ser	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.1438C>T	p.Pro480Ser	missense	Exon 6 of 6	ENSP00000367125.2	Q6NV75
	GPR153	ENST00000937750.1		c.1465C>T	p.Pro489Ser	missense	Exon 6 of 6	ENSP00000607809.1
	GPR153	ENST00000937749.1		c.1438C>T	p.Pro480Ser	missense	Exon 6 of 6	ENSP00000607808.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147502 Hom.: 0 Cov.: 32

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: 0.0000302

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000110 AC: 1 AN: 908472 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 425528

African (AFR) AF: 0.00 AC: 0 AN: 17422

American (AMR) AF: 0.00 AC: 0 AN: 3410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7296

East Asian (EAS) AF: 0.00 AC: 0 AN: 8376

South Asian (SAS) AF: 0.00 AC: 0 AN: 18004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2010

European-Non Finnish (NFE) AF: 0.00000123 AC: 1 AN: 811536

Other (OTH) AF: 0.00 AC: 0 AN: 31788

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147502 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71838

African (AFR) AF: 0.00 AC: 0 AN: 40944

American (AMR) AF: 0.00 AC: 0 AN: 14848

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000302 AC: 2 AN: 66254

Other (OTH) AF: 0.00 AC: 0 AN: 2038

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.075
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.93
DEOGEN2	Benign	0.0063	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.92
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.057
Sift	Benign	0.60	T
Sift4G	Uncertain	0.024	D
Polyphen		0.0050	B
Vest4		0.049
MutPred		0.30		Gain of phosphorylation at P480 (P = 0.0024)
MVP		0.30
MPC		0.36
ClinPred		0.12	T
GERP RS		3.8
Varity_R		0.098
gMVP		0.48
Mutation Taster		=95/5	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: rs889580535; hg19: chr1-6309790;