chr14-88010954-T-C

Position:

• chr14-88010954-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003608.4(GPR65):​c.107T>C​(p.Leu36Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GPR65 NM_003608.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.91

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]

ENSG00000258407 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR65	NM_003608.4	c.107T>C	p.Leu36Pro	missense_variant	2/2	ENST00000267549.5	NP_003599.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR65	ENST00000267549.5	c.107T>C	p.Leu36Pro	missense_variant	2/2	1	NM_003608.4	ENSP00000267549.3
ENSG00000258407	ENST00000554433.1	n.164A>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458256 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 725664

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.107T>C (p.L36P) alteration is located in exon 2 (coding exon 1) of the GPR65 gene. This alteration results from a T to C substitution at nucleotide position 107, causing the leucine (L) at amino acid position 36 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.4	M
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.2	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.85		Loss of stability (P = 0.0591);
MVP		0.75
MPC		0.86
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.87

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: chr14-88477298;