rs188462546

chr14-76499932-T-C

Variant summary

Our verdict is Benign. Variant got -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. 12/17 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 ENST00000509242.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: -0.140

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 -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: {Uncertain_significance=2, Likely_benign=3, 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.*1474T>C		3_prime_UTR_variant	7/7		NM_001379180.1	P1
	ENST00000554926.1	n.414+2225A>G		intron_variant, non_coding_transcript_variant		3

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

GnomAD3 exomes AF: 0.00318 AC: 799 AN: 250906 Hom.: 2 AF XY: 0.00338 AC XY: 458 AN XY: 135586

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

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.: 4 Cov.: 33 AF XY: 0.00359 AC XY: 267 AN XY: 74446

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.: 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

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	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). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2017	- -

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

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. -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	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
MetaRNN	Benign	0.0092	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N
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

Splicing

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

Publications

LitVar

Other links and lift over

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