chr14-76439434-C-A

Variant names:

• chr14-76439434-C-A
• rs35544003
• NM_001379180.1:c.144C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001379180.1(ESRRB):​c.144C>A​(p.Ile48Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0647 in 1,613,444 control chromosomes in the GnomAD database, including 4,914 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (605 hom., cov: 33)
  • Exomes 𝑓: 0.063 (4309 hom.)
• Consequence: ESRRB NM_001379180.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.310
• Publications: 17 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BP6: Variant 14-76439434-C-A is Benign according to our data. Variant chr14-76439434-C-A is described in ClinVar as [Benign]. Clinvar id is 45001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.144C>A	p.Ile48Ile	synonymous_variant	Exon 2 of 7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1	c.144C>A	p.Ile48Ile	synonymous_variant	Exon 2 of 7		NM_001379180.1	ENSP00000493776.1

Frequencies

GnomAD3 genomes AF: 0.0762 AC: 11603 AN: 152184 Hom.: 601 Cov.: 33

Gnomad AFR AF: 0.0918

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0855

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0526

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0537

Gnomad OTH AF: 0.0626

GnomAD2 exomes AF: 0.0869 AC: 21504 AN: 247442 AF XY: 0.0861

Gnomad AFR exome AF: 0.0902

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.249

Gnomad FIN exome AF: 0.0570

Gnomad NFE exome AF: 0.0574

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0635 AC: 92781 AN: 1461142 Hom.: 4309 Cov.: 36 AF XY: 0.0652 AC XY: 47392 AN XY: 726870

African (AFR) AF: 0.0905 AC: 3031 AN: 33476

American (AMR) AF: 0.0885 AC: 3956 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 632 AN: 26130

East Asian (EAS) AF: 0.247 AC: 9818 AN: 39692

South Asian (SAS) AF: 0.134 AC: 11527 AN: 86246

European-Finnish (FIN) AF: 0.0590 AC: 3125 AN: 52946

Middle Eastern (MID) AF: 0.0347 AC: 200 AN: 5764

European-Non Finnish (NFE) AF: 0.0505 AC: 56137 AN: 1111806

Other (OTH) AF: 0.0721 AC: 4355 AN: 60370

GnomAD4 genome AF: 0.0764 AC: 11633 AN: 152302 Hom.: 605 Cov.: 33 AF XY: 0.0799 AC XY: 5950 AN XY: 74474

African (AFR) AF: 0.0921 AC: 3830 AN: 41568

American (AMR) AF: 0.0856 AC: 1310 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.256 AC: 1323 AN: 5158

South Asian (SAS) AF: 0.137 AC: 662 AN: 4824

European-Finnish (FIN) AF: 0.0526 AC: 559 AN: 10630

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0537 AC: 3654 AN: 68028

Other (OTH) AF: 0.0619 AC: 131 AN: 2116

Alfa AF: 0.0546 Hom.: 105

Bravo AF: 0.0757

Asia WGS AF: 0.195 AC: 676 AN: 3478

EpiCase AF: 0.0455

EpiControl AF: 0.0439

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ile27Ile in Exon 04 of ESRRB: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue, is not located within the splice consensus sequence, and has been identified in 8.1% (301/3718) of Af rican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35544003). -

not provided Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive nonsyndromic hearing loss 35 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	4.4
DANN	Benign	0.91
PhyloP100		-0.31
PromoterAI		-0.021	Neutral
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35544003; hg19: chr14-76905777; COSMIC: COSV55058640; COSMIC: COSV55058640;