rs781612689

Positions:

• chr14-76439467-G-A
• chr14-76439467-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_001379180.1(ESRRB):​c.177G>A​(p.Ser59=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000077 in 1,610,502 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: ESRRB NM_001379180.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.518

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 14-76439467-G-A is Benign according to our data. Variant chr14-76439467-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 314481.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-0.518 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.177G>A	p.Ser59=	synonymous_variant	2/7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1	c.177G>A	p.Ser59=	synonymous_variant	2/7		NM_001379180.1	ENSP00000493776	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000581

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000438 AC: 105 AN: 239460 Hom.: 0 AF XY: 0.000343 AC XY: 45 AN XY: 131380

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000625

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000930

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000761 AC: 111 AN: 1458202 Hom.: 0 Cov.: 36 AF XY: 0.0000620 AC XY: 45 AN XY: 725424

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000996

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152300 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74466

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000583

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 07, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 10, 2023	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Oct 09, 2016

p.Ser38Ser in Exon 4 of ESRRB: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 0.3% (36/11138) of Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broad institute.org; dbSNP rs781612689). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	9.7
DANN	Benign	0.92

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: rs781612689; hg19: chr14-76905810;