19-45590982-G-C

Variant names:

• chr19-45590982-G-C
• NM_005282.3:c.885C>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005282.3(GPR4):​c.885C>G​(p.Ser295Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. S295N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GPR4 NM_005282.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.55

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041625947).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GPR4	NM_005282.3	c.885C>G	p.Ser295Arg	missense_variant	Exon 2 of 2	ENST00000323040.5	NP_005273.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPR4	ENST00000323040.5	c.885C>G	p.Ser295Arg	missense_variant	Exon 2 of 2	1	NM_005282.3	ENSP00000319744.3
OPA3	ENST00000544371.1	c.-18+11113C>G		intron_variant	Intron 1 of 1	2		ENSP00000442839.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.885C>G (p.S295R) alteration is located in exon 2 (coding exon 1) of the GPR4 gene. This alteration results from a C to G substitution at nucleotide position 885, causing the serine (S) at amino acid position 295 to be replaced by an arginine (R). 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	0.22
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.38
DANN	Benign	0.76
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0052	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.017
Sift	Benign	0.74	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.27		Gain of MoRF binding (P = 0.0427);
MVP		0.22
MPC		1.1
ClinPred		0.035	T
GERP RS		-1.6
Varity_R		0.029
gMVP		0.37

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: chr19-46094240;