7-1091999-A-T

Variant names:

• chr7-1091999-A-T
• rs1219921770
• NM_001098201.3:c.271A>T

Variant summary

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

The NM_001098201.3(GPER1):​c.271A>T​(p.Met91Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,774 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 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: 0.0000034 (0 hom.)
• Consequence: GPER1 NM_001098201.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.69

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]

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

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 rank	MANE	Protein	UniProt
GPER1	NM_001098201.3	c.271A>T	p.Met91Leu	missense_variant	Exon 2 of 2	ENST00000397088.4	NP_001091671.1
C7orf50	NM_001318252.2	c.129+35258T>A		intron_variant	Intron 2 of 4	ENST00000397098.8	NP_001305181.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GPER1	ENST00000397088.4	c.271A>T	p.Met91Leu	missense_variant	Exon 2 of 2	1	NM_001098201.3	ENSP00000380277.3
C7orf50	ENST00000397098.8	c.129+35258T>A		intron_variant	Intron 2 of 4	1	NM_001318252.2	ENSP00000380286.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251388 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461774 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.271A>T (p.M91L) alteration is located in exon 3 (coding exon 1) of the GPER1 gene. This alteration results from a A to T substitution at nucleotide position 271, causing the methionine (M) at amino acid position 91 to be replaced by a leucine (L). 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	0.21
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.085	T;T;T;T;T
Eigen	Benign	-0.0058
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	.;T;.;.;T
M_CAP	Benign	0.0048	T
MetaRNN	Uncertain	0.57	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;L;L;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.91	N;N;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.80	T;T;T;T;.
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.053	B;B;B;B;.
Vest4		0.69
MutPred		0.59		Loss of ubiquitination at K90 (P = 0.0801);Loss of ubiquitination at K90 (P = 0.0801);Loss of ubiquitination at K90 (P = 0.0801);Loss of ubiquitination at K90 (P = 0.0801);Loss of ubiquitination at K90 (P = 0.0801);
MVP		0.29
MPC		0.56
ClinPred		0.26	T
GERP RS		5.5
Varity_R		0.47
gMVP		0.90

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: rs1219921770; hg19: chr7-1131635;