1-6249729-G-A

Position:

• chr1-6249729-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000377893.3(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. 14/21 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 ENST00000377893.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.636

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0051596463).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 217 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR153	NM_207370.4	c.1439C>T	p.Pro480Leu	missense_variant	6/6	ENST00000377893.3	NP_997253.2
GPR153	XM_011541434.4	c.1439C>T	p.Pro480Leu	missense_variant	6/6		XP_011539736.1
GPR153	XM_017001250.2	c.1439C>T	p.Pro480Leu	missense_variant	5/5		XP_016856739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR153	ENST00000377893.3	c.1439C>T	p.Pro480Leu	missense_variant	6/6	1	NM_207370.4	ENSP00000367125	P1

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

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

Gnomad4 AFR exome AF: 0.000230

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000121

Gnomad4 SAS exome AF: 0.0183

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000506

Gnomad4 OTH exome AF: 0.00129

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

Gnomad4 AFR AF: 0.000438

Gnomad4 AMR AF: 0.0000672

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.0151

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000604

Gnomad4 OTH AF: 0.000971

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000215

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.1439C>T (p.P480L) alteration is located in exon 6 (coding exon 5) of the GPR153 gene. This alteration results from a C to T substitution at nucleotide position 1439, causing the proline (P) at amino acid position 480 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	N
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

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: rs1050565050; hg19: chr1-6309789;