rs79273904

chr14-76482674-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_001379180.1(ESRRB):c.765G>A(p.Glu255=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000719 in 1,614,172 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00077 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (17 hom.)
• Consequence: ESRRB NM_001379180.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.75

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 14-76482674-G-A is Benign according to our data. Variant chr14-76482674-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 163420.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000768 (117/152304) while in subpopulation EAS AF= 0.0184 (95/5170). AF 95% confidence interval is 0.0154. There are 2 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• 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.765G>A	p.Glu255=	synonymous_variant	5/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.765G>A	p.Glu255=	synonymous_variant	5/7		NM_001379180.1	P1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 116 AN: 152186 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00159 AC: 400 AN: 251464 Hom.: 7 AF XY: 0.00152 AC XY: 206 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0169

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000713 AC: 1043 AN: 1461868 Hom.: 17 Cov.: 32 AF XY: 0.000729 AC XY: 530 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0181

Gnomad4 SAS exome AF: 0.000383

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.000811

GnomAD4 genome AF: 0.000768 AC: 117 AN: 152304 Hom.: 2 Cov.: 32 AF XY: 0.000779 AC XY: 58 AN XY: 74480

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0184

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000287 Hom.: 1

Bravo AF: 0.000846

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2018	- -

Autosomal recessive nonsyndromic hearing loss 35 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 03, 2015

p.Glu234Glu in Exon 07 of ESRRB: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 1.7% (148/8644) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs79273904). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
Cadd	Benign	6.8
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79273904; hg19: chr14-76949017; COSMIC: COSV99835242;