3-71754185-G-A

Variant summary

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

The NM_018971.3(GPR27):c.136G>A(p.Glu46Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000215 in 1,438,076 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

GPR27
NM_018971.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.35

Variant links:

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]

GPR27 links:

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]

EIF4E3 links:

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=0.2566961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GPR27	NM_018971.3 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	1/1	ENST00000304411.3
EIF4E3	NM_001134649.3 linkuse as main transcript	c.-291+30C>T		intron_variant
EIF4E3	NM_173359.5 linkuse as main transcript	c.-291+459C>T		intron_variant
EIF4E3	XM_047448063.1 linkuse as main transcript	c.-413+30C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPR27	ENST00000304411.3 linkuse as main transcript	c.136G>A	p.Glu46Lys	missense_variant	1/1		NM_018971.3	P1
EIF4E3	ENST00000421769.6 linkuse as main transcript	c.-291+459C>T		intron_variant		1			Q8N5X7-2
EIF4E3	ENST00000448225.5 linkuse as main transcript	c.-291+30C>T		intron_variant		5			Q8N5X7-2
EIF4E3	ENST00000496214.6 linkuse as main transcript	c.-291+30C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000121

AC:

AN:

148672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000270

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000348

AC:

AN:

172588

Hom.:

AF XY:

0.0000305

AC XY:

AN XY:

98392

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000622

Gnomad OTH exome

AF:

0.000255

GnomAD4 exome

AF:

0.000226

AC:

291

AN:

1289404

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

128

AN XY:

642898

show subpopulations

Gnomad4 AFR exome

AF:

0.0000382

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:

0.000277

Gnomad4 OTH exome

AF:

0.000160

GnomAD4 genome

AF:

0.000121

AC:

AN:

148672

Hom.:

Cov.:

AF XY:

0.000124

AC XY:

AN XY:

72488

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000270

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000117

Hom.:

Bravo

AF:

0.000125

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000510

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2022

The c.136G>A (p.E46K) alteration is located in exon 1 (coding exon 1) of the GPR27 gene. This alteration results from a G to A substitution at nucleotide position 136, causing the glutamic acid (E) at amino acid position 46 to be replaced by a lysine (K). 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

Uncertain

0.51

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.82

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.28

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.013

Polyphen

0.22

Vest4

0.17

MVP

0.15

ClinPred

0.28

GERP RS

1.9

Varity_R

0.41

gMVP

0.29

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over