chr4-8581136-C-T

Variant names:

• chr4-8581136-C-T
• rs746130838
• NM_080819.5:c.154C>T

Variant summary

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

The NM_080819.5(GPR78):​c.154C>T​(p.His52Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000156 in 1,605,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: GPR78 NM_080819.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55
• Publications: 1 publications found

Genes affected

GPR78 (HGNC:4528): (G protein-coupled receptor 78) The protein encoded by this gene belongs to the G protein-coupled receptor family, which contain 7 transmembrane domains and transduce extracellular signals through heterotrimeric G proteins. This is an orphan receptor, which displays significant level of constitutive activity. Association analysis shows preliminary evidence for the involvement of this gene in susceptibility to bipolar affective disorder and schizophrenia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080819.5. 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
	GPR78	NM_080819.5	MANE Select	c.154C>T	p.His52Tyr	missense	Exon 1 of 3	NP_543009.2
	GPR78	NR_045511.3		n.313+432C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPR78	ENST00000382487.5	TSL:1 MANE Select	c.154C>T	p.His52Tyr	missense	Exon 1 of 3	ENSP00000371927.4	Q96P69
	GPR78	ENST00000509216.1	TSL:1	n.468+432C>T		intron	N/A
	GPR78	ENST00000514302.5	TSL:2	n.154C>T		non_coding_transcript_exon	Exon 2 of 14	ENSP00000424326.1	D6RB95

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000206 AC: 5 AN: 242446 AF XY: 0.0000378

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1452820 Hom.: 0 Cov.: 36 AF XY: 0.0000166 AC XY: 12 AN XY: 723196

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.0000221 AC: 1 AN: 45164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5504

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111766

Other (OTH) AF: 0.0000332 AC: 2 AN: 60284

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41472

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000498 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.5
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.28
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.99	D
Vest4		0.36
MVP		0.78
MPC		0.28
ClinPred		0.61	D
GERP RS		1.3
Varity_R		0.40
gMVP		0.58
Mutation Taster		=82/18	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: rs746130838; hg19: chr4-8582863; COSMIC: COSV66762641; COSMIC: COSV66762641;