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. 15/23 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

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 FAILED 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

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR153	ENST00000377893.3	c.1439C>T	p.Pro480Leu	missense_variant	Exon 6 of 6	1	NM_207370.4	ENSP00000367125.2

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

Gnomad4 AFR exome AF: 0.000230 AC: 4 AN: 17384

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 3370

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 7242

Gnomad4 EAS exome AF: 0.000121 AC: 1 AN: 8232

Gnomad4 SAS exome AF: 0.0183 AC: 329 AN: 17986

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 8484

Gnomad4 NFE exome AF: 0.0000506 AC: 41 AN: 810560

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.000438 AC: 0.000438468 AN: 0.000438468

Gnomad4 AMR AF: 0.0000672 AC: 0.0000672314 AN: 0.0000672314

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000196 AC: 0.000195925 AN: 0.000195925

Gnomad4 SAS AF: 0.0151 AC: 0.0151389 AN: 0.0151389

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000604 AC: 0.0000603737 AN: 0.0000603737

Gnomad4 OTH AF: 0.000971 AC: 0.000970874 AN: 0.000970874

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

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs1050565050; hg19: chr1-6309789;