rs188462546

Variant names:

• chr14-76499932-T-C
• rs188462546
• ENST00000509242.5:c.1366T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000509242.5(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. 12/18 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 0.0035 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (24 hom.)
• Consequence: ESRRB ENST00000509242.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.140
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 35

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259124 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.*1474T>C		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	c.*1474T>C		3_prime_UTR_variant	Exon 7 of 7		NM_001379180.1	ENSP00000493776.1

Frequencies

GnomAD3 genomes AF: 0.00353 AC: 537 AN: 152148 Hom.: 4 Cov.: 33

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

GnomAD2 exomes AF: 0.00318 AC: 799 AN: 250906 AF XY: 0.00338

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 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.: 24 Cov.: 31 AF XY: 0.00449 AC XY: 3264 AN XY: 727058

African (AFR) AF: 0.000956 AC: 32 AN: 33478

American (AMR) AF: 0.00434 AC: 194 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.000992 AC: 53 AN: 53410

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00556 AC: 6180 AN: 1111938

Other (OTH) AF: 0.00444 AC: 268 AN: 60396

GnomAD4 genome AF: 0.00353 AC: 537 AN: 152266 Hom.: 4 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74446

African (AFR) AF: 0.00137 AC: 57 AN: 41550

American (AMR) AF: 0.00791 AC: 121 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000754 AC: 8 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00501 AC: 341 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00442 Hom.: 2

Bravo AF: 0.00392

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00488 AC: 42

ExAC AF: 0.00322 AC: 391

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00545

EpiControl AF: 0.00409

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:2

Jul 17, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Jul 07, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Autosomal recessive nonsyndromic hearing loss 35 Uncertain:1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ESRRB: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.35	T
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	N
LIST_S2	Benign	0.24	.;T
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		-0.14
PrimateAI	Benign	0.33	T
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	T
GERP RS		-1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.055
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs188462546; hg19: chr14-76966275; COSMIC: COSV55066101;