chr16-20032121-T-A

Position:

• chr16-20032121-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001002911.4(GPR139):​c.676A>T​(p.Thr226Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR139 NM_001002911.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR139	NM_001002911.4	c.676A>T	p.Thr226Ser	missense_variant	2/2	ENST00000570682.2	NP_001002911.1
GPR139	NM_001318483.1	c.397A>T	p.Thr133Ser	missense_variant	3/3		NP_001305412.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR139	ENST00000570682.2	c.676A>T	p.Thr226Ser	missense_variant	2/2	1	NM_001002911.4	ENSP00000458791.2
GPR139	ENST00000326571.7	n.*622A>T		non_coding_transcript_exon_variant	3/3	1		ENSP00000370779.5
GPR139	ENST00000326571.7	n.*622A>T		3_prime_UTR_variant	3/3	1		ENSP00000370779.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

Nov 02, 2023

The c.676A>T (p.T226S) alteration is located in exon 2 (coding exon 2) of the GPR139 gene. This alteration results from a A to T substitution at nucleotide position 676, causing the threonine (T) at amino acid position 226 to be replaced by a serine (S). 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	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L
PrimateAI	Uncertain	0.77	T
Sift4G	Benign	0.28	T
Polyphen		0.56	P
Vest4		0.85
MutPred		0.65		Loss of helix (P = 0.0558);
MVP		0.79
MPC		1.1
ClinPred		0.94	D
GERP RS		5.6
Varity_R		0.15
gMVP		0.80

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: chr16-20043443;