19-45591284-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005282.3(GPR4):​c.583G>A​(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A195V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

GPR4
NM_005282.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.218
Variant links:
Genes affected
GPR4 (HGNC:4497): (G protein-coupled receptor 4) Enables G protein-coupled receptor activity. Involved in several processes, including G protein-coupled receptor signaling pathway; positive regulation of Rho protein signal transduction; and response to acidic pH. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]
OPA3 (HGNC:8142): (outer mitochondrial membrane lipid metabolism regulator OPA3) The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.069627196).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GPR4NM_005282.3 linkc.583G>A p.Ala195Thr missense_variant Exon 2 of 2 ENST00000323040.5 NP_005273.1 P46093

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GPR4ENST00000323040.5 linkc.583G>A p.Ala195Thr missense_variant Exon 2 of 2 1 NM_005282.3 ENSP00000319744.3 P46093
OPA3ENST00000544371.1 linkc.-18+10811G>A intron_variant Intron 1 of 1 2 ENSP00000442839.1 B4DK77

Frequencies

GnomAD3 genomes
AF:
0.000145
AC:
22
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
249100
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135116
show subpopulations
Gnomad AFR exome
AF:
0.000437
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.0000212
AC:
31
AN:
1460664
Hom.:
0
Cov.:
31
AF XY:
0.0000193
AC XY:
14
AN XY:
726632
show subpopulations
Gnomad4 AFR exome
AF:
0.000568
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000145
AC:
22
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.000121
AC XY:
9
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.000458
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000479
Alfa
AF:
0.000354
Hom.:
0
Bravo
AF:
0.000181
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 28, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.583G>A (p.A195T) alteration is located in exon 2 (coding exon 1) of the GPR4 gene. This alteration results from a G to A substitution at nucleotide position 583, causing the alanine (A) at amino acid position 195 to be replaced by a threonine (T). 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
Benign
0.082
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
T
Eigen
Benign
-0.52
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.60
D
LIST_S2
Benign
0.38
T
M_CAP
Benign
0.0095
T
MetaRNN
Benign
0.070
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.12
N
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-0.48
N
REVEL
Benign
0.095
Sift
Benign
0.38
T
Sift4G
Benign
0.47
T
Polyphen
0.0030
B
Vest4
0.034
MVP
0.38
MPC
0.94
ClinPred
0.039
T
GERP RS
4.2
Varity_R
0.077
gMVP
0.63

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778403402; hg19: chr19-46094542; API