1-6249469-C-A

Variant names:

• chr1-6249469-C-A
• rs568629267
• NM_207370.4:c.1699G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207370.4(GPR153):​c.1699G>T​(p.Ala567Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,170,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A567T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: GPR153 NM_207370.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.804
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071427435).

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.1699G>T	p.Ala567Ser	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.1699G>T	p.Ala567Ser	missense	Exon 6 of 6	ENSP00000367125.2	Q6NV75
	GPR153	ENST00000937750.1		c.1726G>T	p.Ala576Ser	missense	Exon 6 of 6	ENSP00000607809.1
	GPR153	ENST00000937749.1		c.1699G>T	p.Ala567Ser	missense	Exon 6 of 6	ENSP00000607808.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000256 AC: 3 AN: 1170280 Hom.: 0 Cov.: 32 AF XY: 0.00000352 AC XY: 2 AN XY: 568462

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23260

American (AMR) AF: 0.00 AC: 0 AN: 9336

Ashkenazi Jewish (ASJ) AF: 0.0000639 AC: 1 AN: 15642

East Asian (EAS) AF: 0.00 AC: 0 AN: 26610

South Asian (SAS) AF: 0.0000232 AC: 1 AN: 43188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3334

European-Non Finnish (NFE) AF: 0.00000103 AC: 1 AN: 974678

Other (OTH) AF: 0.00 AC: 0 AN: 47340

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.96
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.38	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.80
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.037
Sift	Uncertain	0.023	D
Sift4G	Benign	0.087	T
Polyphen		0.18	B
Vest4		0.12
MutPred		0.15		Gain of relative solvent accessibility (P = 0.0098)
MVP		0.17
MPC		0.43
ClinPred		0.11	T
GERP RS		2.8
Varity_R		0.098
gMVP		0.29
Mutation Taster		=92/8	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: rs568629267; hg19: chr1-6309529;