Variant 11-64314842-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_004451.5(ESRRA):c.673G>A(p.Val225Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000031 in 1,612,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

ESRRA
NM_004451.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.24

Variant links:

Genes affected

ESRRA (HGNC:3471): (estrogen related receptor alpha) The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1. [provided by RefSeq, Jun 2019]

ESRRA 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=0.2074447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESRRA	NM_004451.5 linkuse as main transcript	c.673G>A	p.Val225Met	missense_variant	5/7	ENST00000000442.11	NP_004442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESRRA	ENST00000000442.11 linkuse as main transcript	c.673G>A	p.Val225Met	missense_variant	5/7	1	NM_004451.5	ENSP00000000442	P4	P11474-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

248192

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

134736

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:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000322

AC:

AN:

1460016

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726336

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

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

Mar 11, 2024

The c.673G>A (p.V225M) alteration is located in exon 5 (coding exon 4) of the ESRRA gene. This alteration results from a G to A substitution at nucleotide position 673, causing the valine (V) at amino acid position 225 to be replaced by a methionine (M). 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

0.20

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

.;T;.;T

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.91

D;.;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

0.20

MutationAssessor

Benign

-0.73

.;N;.;N

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.74

PROVEAN

Benign

0.61

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.033

D;D;D;D

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.43

B;P;.;P

Vest4

0.19

MutPred

0.59

.;Gain of disorder (P = 0.0887);.;Gain of disorder (P = 0.0887);

MVP

0.86

MPC

0.61

ClinPred

0.14

GERP RS

4.0

Varity_R

0.31

gMVP

0.49

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