16-20031925-C-A

Variant names:

• chr16-20031925-C-A
• rs144836581
• NM_001002911.4:c.872G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001002911.4(GPR139):​c.872G>T​(p.Arg291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R291Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GPR139 NM_001002911.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

GPR139 (HGNC:19995): (G protein-coupled receptor 139) This gene encodes a member of the rhodopsin family of G-protein-coupled receptors. The encoded protein is almost exclusively expressed in the central nervous system. L-tryptophan and L-phenylalanine may act as the physiologic ligands of the encoded protein. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.826

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001002911.4. 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
	GPR139	NM_001002911.4	MANE Select	c.872G>T	p.Arg291Leu	missense	Exon 2 of 2	NP_001002911.1	Q6DWJ6
	GPR139	NM_001318483.1		c.593G>T	p.Arg198Leu	missense	Exon 3 of 3	NP_001305412.1	Q6DWJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR139	ENST00000570682.2	TSL:1 MANE Select	c.872G>T	p.Arg291Leu	missense	Exon 2 of 2	ENSP00000458791.2	Q6DWJ6
	GPR139	ENST00000326571.7	TSL:1	n.*818G>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000370779.5	J3KPI8
	GPR139	ENST00000326571.7	TSL:1	n.*818G>T		3_prime_UTR	Exon 3 of 3	ENSP00000370779.5	J3KPI8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461884 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.81	D
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.92
MutPred		0.59		Loss of catalytic residue at R291 (P = 0.0257)
MVP		0.81
MPC		1.3
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.50
gMVP		0.88
Mutation Taster		=50/50

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: rs144836581; hg19: chr16-20043247;