chr3-71754705-T-C

Position:

• chr3-71754705-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018971.3(GPR27):​c.656T>C​(p.Leu219Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GPR27 NM_018971.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.33

Genes affected

GPR27 (HGNC:4482): (G protein-coupled receptor 27) GPR27 is a member of the G protein-coupled receptors (GPCRs), a large family of receptors that have a similar structure characterized by 7 transmembrane domains. Activation of GPCRs by extracellular stimuli such as neurotransmitters, hormones, or light induces an intracellular signaling cascade mediated by heterotrimeric GTP-binding proteins, or G proteins.[supplied by OMIM, May 2010]

EIF4E3 (HGNC:31837): (eukaryotic translation initiation factor 4E family member 3) EIF4E3 belongs to the EIF4E family of translational initiation factors that interact with the 5-prime cap structure of mRNA and recruit mRNA to the ribosome (Joshi et al., 2004 [PubMed 15153109]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GPR27	NM_018971.3	c.656T>C	p.Leu219Pro	missense_variant	1/1	ENST00000304411.3	NP_061844.1
EIF4E3	NM_173359.5	c.-352A>G		5_prime_UTR_variant	1/8		NP_775495.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GPR27	ENST00000304411.3	c.656T>C	p.Leu219Pro	missense_variant	1/1	6	NM_018971.3	ENSP00000303149.2
EIF4E3	ENST00000421769.6	c.-352A>G		5_prime_UTR_variant	1/8	1		ENSP00000411762.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1315958 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 653918

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.: 32

Bravo AF: 0.0000151

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

Nov 09, 2021

The c.656T>C (p.L219P) alteration is located in exon 1 (coding exon 1) of the GPR27 gene. This alteration results from a T to C substitution at nucleotide position 656, causing the leucine (L) at amino acid position 219 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	Benign	0.23
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.1	M
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.58
Sift	Benign	0.035	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.68		Gain of disorder (P = 0.0032);
MVP		0.15
ClinPred		0.99	D
GERP RS		3.3
Varity_R		0.69
gMVP		0.73

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: rs1469528679; hg19: chr3-71803856;