rs201448899

chr14-76500004-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000509242.5(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 ENST00000509242.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:2
• Conservation: PhyloP100: 0.418

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 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=6}.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.*1546C>T		3_prime_UTR_variant	7/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.*1546C>T		3_prime_UTR_variant	7/7		NM_001379180.1	P1
	ENST00000554926.1	n.414+2153G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000880 AC: 134 AN: 152194 Hom.: 2 Cov.: 33

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.: 0 AF XY: 0.000650 AC XY: 63 AN XY: 96970

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.: 2 Cov.: 31 AF XY: 0.000911 AC XY: 640 AN XY: 702578

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.: 2 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74462

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.: 0

Bravo AF: 0.00117

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 5

ExAC AF: 0.000524 AC: 62

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	ESRRB: BP4, BS2 -

Autosomal recessive nonsyndromic hearing loss 35 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 05, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 02, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 20, 2016

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	T
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	N
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0076	T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.55	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.21	T
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	T
GERP RS		1.4
gMVP		0.12

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs201448899; hg19: chr14-76966347; COSMIC: COSV55059680; COSMIC: COSV55059680;