Genetic Variant NM_080819.5:c.277G>C (chr4-8581259-G-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_080819.5(GPR78):c.277G>C(p.Ala93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,862 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A93S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GPR78
NM_080819.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.838

Publications

2 publications found

Variant links:

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]

GPR78 links:

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ACMG classification

Classification was made for transcript

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.277G>C	p.Ala93Pro	missense	Exon 1 of 3	NP_543009.2
	GPR78	NR_045511.3		n.313+555G>C		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GPR78	ENST00000382487.5	TSL:1 MANE Select	c.277G>C	p.Ala93Pro	missense	Exon 1 of 3	ENSP00000371927.4	Q96P69
GPR78	ENST00000509216.1	TSL:1	n.468+555G>C		intron	N/A
GPR78	ENST00000514302.5	TSL:2	n.277G>C		non_coding_transcript_exon	Exon 2 of 14	ENSP00000424326.1	D6RB95

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000482

AC:

AN:

207354

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000314

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438862

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.0000233

AC:

AN:

42960

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39304

South Asian (SAS)

AF:

0.00

AC:

AN:

84522

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106000

Other (OTH)

AF:

0.00

AC:

AN:

59756

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Benign

-0.088

Eigen_PC

Benign

-0.26

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.82

M_CAP

Benign

0.0050

MetaRNN

Uncertain

0.43

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.3

PhyloP100

0.84

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-2.4

REVEL

Benign

0.21

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.043

Polyphen

1.0

Vest4

0.29

MutPred

0.51

Loss of glycosylation at S91 (P = 0.0445)

MVP

0.54

MPC

0.33

ClinPred

0.62

GERP RS

0.77

Varity_R

0.76

gMVP

0.74

Mutation Taster

=73/27

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over