chr14-76439474-G-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001379180.1(ESRRB):c.184G>A(p.Ala62Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,612,032 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

ESRRB
NM_001379180.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.87

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.18518233).

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000197 (3/152186) while in subpopulation EAS AF= 0.00058 (3/5174). AF 95% confidence interval is 0.000157. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1 link	c.184G>A	p.Ala62Thr	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 link	c.184G>A	p.Ala62Thr	missense_variant	Exon 2 of 7		NM_001379180.1	ENSP00000493776.1		A0A2R8Y491

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

242526

Hom.:

AF XY:

0.0000753

AC XY:

AN XY:

132796

show subpopulations

Gnomad AFR exome

AF:

0.0000685

Gnomad AMR exome

AF:

0.000495

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000339

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000168

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1459846

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

726306

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000302

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000907

ExAC

AF:

0.0000415

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.121G>A (p.A41T) alteration is located in exon 4 (coding exon 1) of the ESRRB gene. This alteration results from a G to A substitution at nucleotide position 121, causing the alanine (A) at amino acid position 41 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 41 of the ESRRB protein (p.Ala41Thr). This variant is present in population databases (rs775825368, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ESRRB-related conditions. ClinVar contains an entry for this variant (Variation ID: 1367448). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0032

T;.;.;.

Eigen

Benign

0.19

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.19

T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Benign

1.6

.;L;.;L

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.080

N;N;.;N

REVEL

Uncertain

0.45

Sift

Benign

0.42

T;T;.;T

Sift4G

Benign

0.55

.;T;.;T

Polyphen

0.35

B;.;.;.

Vest4

0.47, 0.47

MutPred

0.17

Loss of helix (P = 0.0167);.;.;.;

MVP

0.78

MPC

0.43

ClinPred

0.055

GERP RS

5.1

gMVP

0.51

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over