chr14-76500004-C-T

Variant names:

Variant summary

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

The NM_004452.4(ESRRB):c.1438C>T(p.Pro480Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000947 in 1,573,048 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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 0.00088 ( 2 hom., cov: 33)

Exomes 𝑓: 0.00095 ( 2 hom. )

Consequence

ESRRB
NM_004452.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:2

Conservation

PhyloP100: 0.418

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:

ENSG00000259124 (HGNC:):

ENSG00000259124 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=0.007597655).

BP6

Variant 14-76500004-C-T is Benign according to our data. Variant chr14-76500004-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163425.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00088 (134/152312) while in subpopulation AMR AF= 0.00189 (29/15306). AF 95% confidence interval is 0.00136. There are 2 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1 link	c.*1546C>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1 link	c.*1546C>T		3_prime_UTR_variant	Exon 7 of 7		NM_001379180.1	ENSP00000493776.1		A0A2R8Y491

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00121

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000670

AC:

123

AN:

183596

Hom.:

AF XY:

0.000650

AC XY:

AN XY:

96970

show subpopulations

Gnomad AFR exome

AF:

0.000276

Gnomad AMR exome

AF:

0.00114

Gnomad ASJ exome

AF:

0.000678

Gnomad EAS exome

AF:

0.0000738

Gnomad SAS exome

AF:

0.000411

Gnomad FIN exome

AF:

0.000109

Gnomad NFE exome

AF:

0.000826

Gnomad OTH exome

AF:

0.00160

GnomAD4 exome

AF:

0.000954

AC:

1355

AN:

1420736

Hom.:

Cov.:

AF XY:

0.000911

AC XY:

640

AN XY:

702578

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.000631

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000284

Gnomad4 FIN exome

AF:

0.000156

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152312

Hom.:

Cov.:

AF XY:

0.000806

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00121

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.000524

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Feb 06, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the ESRRB protein (p.Pro480Ser). This variant is present in population databases (rs201448899, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Meniere disease (PMID: 30828346). ClinVar contains an entry for this variant (Variation ID: 163425). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Oct 20, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ESRRB: BS1:Supporting -

Autosomal recessive nonsyndromic hearing loss 35

Uncertain:3

Mar 02, 2019

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Mar 05, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The ESRRB c.1438C>T; p.Pro480Ser variant (rs201448899) is reported in the literature in a cohort of individuals affected with Meniere's disease, though it was not considered to be disease-causing (Gallego-Martinez 2019). This variant is found in the Latino population with an overall allele frequency of 0.11% (31/27214 alleles) in the Genome Aggregation Database. The proline at codon 480 is weakly conserved but computational analyses (SIFT: damaging, PolyPhen-2: benign) predict conflicting effects of this variant on protein structure/function. Given the lack of clinical and functional data, the significance of the p.Pro480Ser variant is uncertain at this time. References: Gallego-Martinez A et al. Excess of Rare Missense Variants in Hearing Loss Genes in Sporadic Meniere Disease. Front. Genet. 2019 Feb 15;10:76. -

not specified

Uncertain:2

Dec 17, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ESRRB c.1438C>T (p.Pro480Ser) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00067 in 183596 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ESRRB causing Autosomal Recessive Nonsyndromic Hearing Loss 35, allowing no conclusion about variant significance. c.1438C>T has been reported in the literature in individual(s) affected with Meniere's disease (Gallego-Martinez_2019) but not Autosomal Recessive Nonsyndromic Hearing Loss 35. These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Nonsyndromic Hearing Loss 35. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30828346). ClinVar contains an entry for this variant (Variation ID: 163425). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jun 20, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Benign. The p.Pro480Ser var iant in ESRRB has been identified by our laboratory in 2 individuals with hearin g loss, including one individual whose hearing loss could be explained by pathog enic variants in a different gene. This variant has also been identified in 0.2% (3/1324) of Latino chromosomes and 0.1% (25/18010) of European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs2 01448899). Although this variant has been seen in the general population, its fr equency is not high enough to rule out a pathogenic role. Computational predicti on tools and conservation analyses suggest that the variant may not impact the p rotein, though this information is not predictive enough to rule out pathogenici ty. In summary, while the clinical significance of the p.Pro480Ser variant is un certain, its frequency suggests that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.25

CADD

Benign

4.0

DANN

Uncertain

0.99

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.32

.;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.0076

T;T

MetaSVM

Benign

-0.32

MutationAssessor

Benign

0.55

N;N

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.11

N;N

REVEL

Benign

0.17

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.46

T;T

Vest4

0.11

MVP

0.41

MPC

0.41

ClinPred

0.014

GERP RS

1.4

gMVP

0.12

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