14-76439496-C-T

Variant names:

• chr14-76439496-C-T
• rs61760172
• NM_001379180.1:c.206C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001379180.1(ESRRB):​c.206C>T​(p.Ala69Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,612,634 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 0.0015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: ESRRB NM_001379180.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 7.85
• Publications: 5 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0066467524).
• BP6: Variant 14-76439496-C-T is Benign according to our data. Variant chr14-76439496-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178342.We mark this variant Benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0015 (229/152358) while in subpopulation AFR AF = 0.00519 (216/41586). AF 95% confidence interval is 0.00463. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.206C>T	p.Ala69Val	missense_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.206C>T	p.Ala69Val	missense_variant	Exon 2 of 7		NM_001379180.1	ENSP00000493776.1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 229 AN: 152238 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000347 AC: 85 AN: 244822 AF XY: 0.000300

Gnomad AFR exome AF: 0.00496

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000363

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1460276 Hom.: 0 Cov.: 36 AF XY: 0.000167 AC XY: 121 AN XY: 726544

African (AFR) AF: 0.00618 AC: 207 AN: 33474

American (AMR) AF: 0.000201 AC: 9 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111858

Other (OTH) AF: 0.000282 AC: 17 AN: 60368

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.00137 AC XY: 102 AN XY: 74496

African (AFR) AF: 0.00519 AC: 216 AN: 41586

American (AMR) AF: 0.000588 AC: 9 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000332 Hom.: 0

Bravo AF: 0.00167

ESP6500AA AF: 0.00364 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000446 AC: 54

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Aug 12, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ESRRB c.143C>T (p.Ala48Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 244822 control chromosomes, predominantly at a frequency of 0.005 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in ESRRB causing Autosomal Recessive Nonsyndromic Hearing Loss 35 phenotype. To our knowledge, no occurrence of c.143C>T in individuals affected with Autosomal Recessive Nonsyndromic Hearing Loss 35 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 178342). Based on the evidence outlined above, the variant was classified as likely benign. -

Apr 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ala48Val in Exon 04 of ESRRB: This variant is not expected to have clinical sign ificance because it has been identified in 0.3% (12/3730) of African American ch romosomes from a broad population by the NHLBI Exome Sequencing Project (http:// evs.gs.washington.edu/EVS; dbSNP rs61760172). -

not provided Benign:2

Oct 02, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 35 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, 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. -

ESRRB-related disorder Benign:1

Jul 17, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T;.;.;.
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.74	T;.;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.0066	T;T;T;T
MetaSVM	Uncertain	-0.073	T
MutationAssessor	Benign	1.7	.;L;.;L
PhyloP100		7.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.85	N;N;.;N
REVEL	Benign	0.27
Sift	Benign	0.054	T;D;.;D
Sift4G	Benign	0.31	.;T;.;T
Polyphen		0.0040	B;.;.;.
Vest4		0.52, 0.52
MVP		0.73
MPC		0.39
ClinPred		0.024	T
GERP RS		5.2
PromoterAI		-0.017	Neutral
gMVP		0.42
Mutation Taster		=56/44	polymorphism

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: rs61760172; hg19: chr14-76905839;