dbSNP rs146351534: ESRRB:p.Val434Ile (chr14-76498393-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001379180.1(ESRRB):c.1300G>A(p.Val434Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,613,450 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.013 ( 187 hom. )

Consequence

ESRRB
NM_001379180.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.85

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 35
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ESRRB links:

ENSG00000259124 (HGNC:):

ENSG00000259124 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.007202655).

BP6

Variant 14-76498393-G-A is Benign according to our data. Variant chr14-76498393-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0107 (1637/152344) while in subpopulation AMR AF = 0.0155 (237/15312). AF 95% confidence interval is 0.0147. There are 14 homozygotes in GnomAd4. There are 803 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379180.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRRB	NM_001379180.1	MANE Select	c.1300G>A	p.Val434Ile	missense	Exon 7 of 7	NP_001366109.1	A0A2R8Y491
ESRRB	NM_004452.4		c.1237G>A	p.Val413Ile	missense	Exon 9 of 11	NP_004443.3
ESRRB	NM_001411038.1		c.1252G>A	p.Val418Ile	missense	Exon 7 of 7	NP_001397967.1	E7EWD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRRB	ENST00000644823.1	MANE Select	c.1300G>A	p.Val434Ile	missense	Exon 7 of 7	ENSP00000493776.1	A0A2R8Y491
ESRRB	ENST00000509242.5	TSL:1	c.1237G>A	p.Val413Ile	missense	Exon 7 of 9	ENSP00000422488.1	O95718-1
ESRRB	ENST00000505752.6	TSL:1	n.1237G>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000423004.1	O95718-2

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1637

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0155

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0179

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0154

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0115

AC:

2872

AN:

249282

AF XY:

0.0116

show subpopulations

Gnomad AFR exome

AF:

0.00231

Gnomad AMR exome

AF:

0.0117

Gnomad ASJ exome

AF:

0.00718

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0193

Gnomad NFE exome

AF:

0.0162

Gnomad OTH exome

AF:

0.0156

GnomAD4 exome

AF:

0.0130

AC:

19017

AN:

1461106

Hom.:

187

Cov.:

AF XY:

0.0128

AC XY:

9328

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33474

American (AMR)

AF:

0.0115

AC:

515

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00670

AC:

175

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.000904

AC:

AN:

86246

European-Finnish (FIN)

AF:

0.0163

AC:

860

AN:

52842

Middle Eastern (MID)

AF:

0.00971

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0149

AC:

16608

AN:

1111900

Other (OTH)

AF:

0.0109

AC:

659

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

1190

2380

3570

4760

5950

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

590

1180

1770

2360

2950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0107

AC:

1637

AN:

152344

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

803

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41584

American (AMR)

AF:

0.0155

AC:

237

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00835

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0179

AC:

190

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0154

AC:

1051

AN:

68030

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0138

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0175

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.0127

AC:

109

ExAC

AF:

0.0110

AC:

1336

EpiCase

AF:

0.0216

EpiControl

AF:

0.0200

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Autosomal recessive nonsyndromic hearing loss 35 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.28

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.82

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0072

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.54

PhyloP100

1.8

PrimateAI

Benign

0.36

PROVEAN

Benign

0.11

REVEL

Benign

0.071

Sift

Benign

0.92

Sift4G

Benign

0.93

Polyphen

0.016

Vest4

0.061

MPC

0.32

ClinPred

0.0072

GERP RS

-5.7

gMVP

0.054

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over