7-1091976-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001098201.3(GPER1):c.248T>C(p.Val83Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,782 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GPER1
NM_001098201.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.64

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.811

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPER1	NM_001098201.3 linkuse as main transcript	c.248T>C	p.Val83Ala	missense_variant	2/2	ENST00000397088.4
C7orf50	NM_001318252.2 linkuse as main transcript	c.129+35281A>G		intron_variant		ENST00000397098.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPER1	ENST00000397088.4 linkuse as main transcript	c.248T>C	p.Val83Ala	missense_variant	2/2	1	NM_001098201.3	P1
C7orf50	ENST00000397098.8 linkuse as main transcript	c.129+35281A>G		intron_variant		1	NM_001318252.2	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251362

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135864

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461782

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727182

show subpopulations

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000113

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

Apr 12, 2022

The c.248T>C (p.V83A) alteration is located in exon 3 (coding exon 1) of the GPER1 gene. This alteration results from a T to C substitution at nucleotide position 248, causing the valine (V) at amino acid position 83 to be replaced by an alanine (A). 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

0.73

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.39

T;T;T;T;T

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

M_CAP

Benign

0.021

MetaRNN

Pathogenic

0.81

D;D;D;D;D

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.6

M;M;M;M;.

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.5

D;D;D;D;.

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D;D;D;.

Sift4G

Uncertain

0.0090

D;D;D;D;D

Polyphen

1.0

D;D;D;D;.

Vest4

0.86

MutPred

0.71

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);

MVP

0.57

MPC

1.4

ClinPred

0.95

GERP RS

5.5

Varity_R

0.84

gMVP

0.88

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