14-76498312-C-T

Variant names:

• chr14-76498312-C-T
• rs61742642
• NM_001379180.1:c.1219C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001379180.1(ESRRB):​c.1219C>T​(p.Pro407Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,613,184 control chromosomes in the GnomAD database, including 4,390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (357 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4033 hom.)
• Consequence: ESRRB NM_001379180.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.91
• Publications: 20 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

ENSG00000259124 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005125433).
• BP6: Variant 14-76498312-C-T is Benign according to our data. Variant chr14-76498312-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.1219C>T	p.Pro407Ser	missense_variant	Exon 7 of 7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1	c.1219C>T	p.Pro407Ser	missense_variant	Exon 7 of 7		NM_001379180.1	ENSP00000493776.1

Frequencies

GnomAD3 genomes AF: 0.0616 AC: 9371 AN: 152182 Hom.: 357 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.0504

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.0704

Gnomad FIN AF: 0.0488

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0680

Gnomad OTH AF: 0.0659

GnomAD2 exomes AF: 0.0766 AC: 18998 AN: 248148 AF XY: 0.0742

Gnomad AFR exome AF: 0.0228

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.0532

Gnomad EAS exome AF: 0.110

Gnomad FIN exome AF: 0.0507

Gnomad NFE exome AF: 0.0692

Gnomad OTH exome AF: 0.0753

GnomAD4 exome AF: 0.0712 AC: 104043 AN: 1460884 Hom.: 4033 Cov.: 35 AF XY: 0.0709 AC XY: 51493 AN XY: 726768

African (AFR) AF: 0.0215 AC: 718 AN: 33472

American (AMR) AF: 0.136 AC: 6086 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 1477 AN: 26122

East Asian (EAS) AF: 0.0961 AC: 3813 AN: 39668

South Asian (SAS) AF: 0.0679 AC: 5853 AN: 86246

European-Finnish (FIN) AF: 0.0527 AC: 2788 AN: 52874

Middle Eastern (MID) AF: 0.0539 AC: 311 AN: 5766

European-Non Finnish (NFE) AF: 0.0708 AC: 78734 AN: 1111786

Other (OTH) AF: 0.0706 AC: 4263 AN: 60356

GnomAD4 genome AF: 0.0615 AC: 9372 AN: 152300 Hom.: 357 Cov.: 32 AF XY: 0.0645 AC XY: 4806 AN XY: 74454

African (AFR) AF: 0.0243 AC: 1012 AN: 41584

American (AMR) AF: 0.129 AC: 1969 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0504 AC: 175 AN: 3472

East Asian (EAS) AF: 0.101 AC: 521 AN: 5164

South Asian (SAS) AF: 0.0705 AC: 340 AN: 4826

European-Finnish (FIN) AF: 0.0488 AC: 518 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0680 AC: 4623 AN: 68014

Other (OTH) AF: 0.0652 AC: 138 AN: 2116

Alfa AF: 0.0637 Hom.: 741

Bravo AF: 0.0637

TwinsUK AF: 0.0763 AC: 283

ALSPAC AF: 0.0747 AC: 288

ESP6500AA AF: 0.0252 AC: 111

ESP6500EA AF: 0.0680 AC: 585

ExAC AF: 0.0712 AC: 8643

Asia WGS AF: 0.108 AC: 375 AN: 3478

EpiCase AF: 0.0677

EpiControl AF: 0.0715

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

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

Pro386Ser in Exon 09 of ESRRB: This variant is not expected to have clinical sig nificance because it has been identified in 6.9% (481/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs35774316). -

not provided Benign:3

Sep 12, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 35 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;.;T;T
MetaRNN	Benign	0.0051	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	.;L;.;L
PhyloP100		7.9
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.4	N;N;.;N
REVEL	Pathogenic	0.68
Sift	Benign	0.45	T;T;.;T
Sift4G	Benign	0.72	.;T;.;T
Polyphen		0.60	P;.;.;.
Vest4		0.34, 0.32
MPC		0.60
ClinPred		0.026	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.55
Mutation Taster		=93/7	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: rs61742642; hg19: chr14-76964655; COSMIC: COSV107224640; COSMIC: COSV107224640;