rs188462546

Positions:

chr14-76499932-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_004452.4(ESRRB):c.1366T>C(p.Phe456Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,613,894 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0035 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 24 hom. )

Consequence

ESRRB
NM_004452.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: -0.140

Variant links:

Genes affected

ESRRB (HGNC:3473): (estrogen related receptor beta) This gene encodes a protein with similarity to the estrogen receptor. Its function is unknown; however, a similar protein in mouse plays an essential role in placental development. [provided by RefSeq, Jul 2008]

ESRRB links:

ESRRB (HGNC:):

ESRRB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009181142).

BP6

Variant 14-76499932-T-C is Benign according to our data. Variant chr14-76499932-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44997.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}. Variant chr14-76499932-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00353 (537/152266) while in subpopulation AMR AF= 0.00791 (121/15302). AF 95% confidence interval is 0.00676. There are 4 homozygotes in gnomad4. There are 267 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESRRB	NM_001379180.1 linkuse as main transcript	c.*1474T>C		3_prime_UTR_variant	7/7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1 linkuse as main transcript	c.*1474T>C		3_prime_UTR_variant	7/7		NM_001379180.1	ENSP00000493776.1		A0A2R8Y491

Frequencies

GnomAD3 genomes

AF:

0.00353

AC:

537

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00792

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00318

AC:

799

AN:

250906

Hom.:

AF XY:

0.00338

AC XY:

458

AN XY:

135586

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00437

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00517

Gnomad OTH exome

AF:

0.00311

GnomAD4 exome

AF:

0.00460

AC:

6730

AN:

1461628

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

3264

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00434

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000992

Gnomad4 NFE exome

AF:

0.00556

Gnomad4 OTH exome

AF:

0.00444

GnomAD4 genome

AF:

0.00353

AC:

537

AN:

152266

Hom.:

Cov.:

AF XY:

0.00359

AC XY:

267

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.00137

Gnomad4 AMR

AF:

0.00791

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00501

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00453

Hom.:

Bravo

AF:

0.00392

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00488

AC:

ExAC

AF:

0.00322

AC:

391

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 31, 2013	Phe456Leu in Exon 10 of ESRRB: This variant is not expected to have clinical sig nificance because it has been identified in 0.5% (32/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project and in 0.5% (12/2178) of chromosomes by the 1000 Genome Project (http://evs.gs.washing ton.edu/EVS; dbSNP rs188462546). -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2017	The F456L variant in the ESRRB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The F456L variant is observed in 58/10360 (0.56%) alleles from individuals of Latino background and in 306/61610 (0.50%) alleles from individuals of non-Finnish European background including 2 homozygous individuals, in the ExAC dataset (Lek et al., 2016). The F456L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. We interpret F456L as a variant of uncertain significance. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2017	- -

Autosomal recessive nonsyndromic hearing loss 35

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	ESRRB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.27

CADD

Benign

1.5

DANN

Benign

0.61

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.24

.;T

MetaRNN

Benign

0.0092

T;T

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.0

N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.24

N;N

REVEL

Uncertain

0.39

Sift

Benign

0.41

T;T

Sift4G

Benign

0.56

T;T

Vest4

0.17

MutPred

0.22

Gain of catalytic residue at F461 (P = 0.0029);Gain of catalytic residue at F461 (P = 0.0029);

MVP

0.82

MPC

0.45

ClinPred

0.0073

GERP RS

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

gMVP

0.055

Splicing

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