14-88011647-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_003608.4(GPR65):c.800G>A(p.Arg267Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GPR65 NM_003608.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0810

Genes affected

GPR65 (HGNC:4517): (G protein-coupled receptor 65) Enables G protein-coupled receptor activity. Involved in several processes, including actin cytoskeleton reorganization; activation of GTPase activity; and positive regulation of stress fiber assembly. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.026246935).
• BP6: Variant 14-88011647-G-A is Benign according to our data. Variant chr14-88011647-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3101821.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPR65	NM_003608.4	c.800G>A	p.Arg267Gln	missense_variant	2/2	ENST00000267549.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR65	ENST00000267549.5	c.800G>A	p.Arg267Gln	missense_variant	2/2	1	NM_003608.4	P1
	ENST00000554433.1	n.96-428C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250998 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461544 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 727108

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000680 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.9
Dann	Benign	0.83
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0075	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.035
Sift	Benign	1.0	T
Sift4G	Benign	0.80	T
Polyphen		0.0	B
Vest4		0.027
MutPred		0.41		Gain of ubiquitination at K266 (P = 0.0913);
MVP		0.50
MPC		0.18
ClinPred		0.021	T
GERP RS		0.94
Varity_R		0.033
gMVP		0.090

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

Other links and lift over

dbSNP: rs771833245; hg19: chr14-88477991; COSMIC: COSV50864456;