14-76439496-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 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:5
• Conservation: PhyloP100: 7.85

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}. Variant chr14-76439496-C-T is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.206C>T	p.Ala69Val	missense_variant	2/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.206C>T	p.Ala69Val	missense_variant	2/7		NM_001379180.1	P1

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

GnomAD3 exomes AF: 0.000347 AC: 85 AN: 244822 Hom.: 0 AF XY: 0.000300 AC XY: 40 AN XY: 133464

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 SAS exome AF: 0.0000655

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

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000282

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

Gnomad4 AFR AF: 0.00519

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000207 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:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	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). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 12, 2016	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Oct 22, 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. -

ESRRB-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 17, 2020

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
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.85	N;N;.;N
REVEL	Benign	0.27
Sift	Benign	0.054	T;D;.;D
Polyphen		0.0040	B;.;.;.
Vest4		0.52, 0.52
MVP		0.73
MPC		0.39
ClinPred		0.024	T
GERP RS		5.2
gMVP		0.42

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: rs61760172; hg19: chr14-76905839;