1-6249501-G-A

Position:

• chr1-6249501-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207370.4(GPR153):​c.1667C>T​(p.Ser556Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000269 in 1,116,270 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GPR153 NM_207370.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061121106).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR153	NM_207370.4	c.1667C>T	p.Ser556Leu	missense_variant	6/6	ENST00000377893.3	NP_997253.2
GPR153	XM_011541434.4	c.1667C>T	p.Ser556Leu	missense_variant	6/6		XP_011539736.1
GPR153	XM_017001250.2	c.1667C>T	p.Ser556Leu	missense_variant	5/5		XP_016856739.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR153	ENST00000377893.3	c.1667C>T	p.Ser556Leu	missense_variant	6/6	1	NM_207370.4	ENSP00000367125.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000269 AC: 3 AN: 1116270 Hom.: 0 Cov.: 32 AF XY: 0.00000187 AC XY: 1 AN XY: 535974

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000318

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 29, 2023

The c.1667C>T (p.S556L) 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 1667, causing the serine (S) at amino acid position 556 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	0.093
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.028
Sift	Benign	0.18	T
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.077
MutPred		0.22		Loss of phosphorylation at S556 (P = 0.0086);
MVP		0.17
MPC		0.27
ClinPred		0.050	T
GERP RS		0.70
Varity_R		0.035
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6309561;