7-1092821-G-A

Variant summary

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

The NM_001098201.3(GPER1):c.1093G>A(p.Glu365Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,460,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

GPER1
NM_001098201.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.85

Variant links:

Genes affected

GPER1 (HGNC:4485): (G protein-coupled estrogen receptor 1) This gene encodes a multi-pass membrane protein that localizes to the endoplasmic reticulum and a member of the G-protein coupled receptor 1 family. This receptor binds estrogen and activates multiple downstream signaling pathways, leading to stimulation of adenylate cyclase and an increase in cyclic AMP levels, while also promoting intracellular calcium mobilization and synthesis of phosphatidylinositol 3,4,5-trisphosphate in the nucleus. This protein therefore plays a role in the rapid nongenomic signaling events widely observed following stimulation of cells and tissues with estrogen. This receptor has been shown to play a role in diverse biological processes, including bone and nervous system development, metabolism, cognition, male fertility and uterine function. [provided by RefSeq, Aug 2017]

GPER1 links:

C7orf50 (HGNC:22421): (chromosome 7 open reading frame 50) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

C7orf50 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=0.14184585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPER1	NM_001098201.3 linkuse as main transcript	c.1093G>A	p.Glu365Lys	missense_variant	2/2	ENST00000397088.4
C7orf50	NM_001318252.2 linkuse as main transcript	c.129+34436C>T		intron_variant		ENST00000397098.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPER1	ENST00000397088.4 linkuse as main transcript	c.1093G>A	p.Glu365Lys	missense_variant	2/2	1	NM_001098201.3	P1
C7orf50	ENST00000397098.8 linkuse as main transcript	c.129+34436C>T		intron_variant		1	NM_001318252.2	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250356

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460920

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.00000756

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 08, 2022

The c.1093G>A (p.E365K) alteration is located in exon 3 (coding exon 1) of the GPER1 gene. This alteration results from a G to A substitution at nucleotide position 1093, causing the glutamic acid (E) at amino acid position 365 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

Benign

0.085

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.36

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.037

T;T;T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.037

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.85

L;L;L;L

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

0.44

N;N;N;N

REVEL

Benign

0.091

Sift

Benign

0.046

D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D

Polyphen

0.12

B;B;B;B

Vest4

0.19

MutPred

0.35

Gain of ubiquitination at E365 (P = 0.0094);Gain of ubiquitination at E365 (P = 0.0094);Gain of ubiquitination at E365 (P = 0.0094);Gain of ubiquitination at E365 (P = 0.0094);

MVP

0.27

MPC

0.49

ClinPred

0.53

GERP RS

4.8

Varity_R

0.11

gMVP

0.64

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