Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000509242.5(ESRRB):c.1427G>A(p.Arg476His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00078 in 1,582,166 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R476C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00080 ( 3 hom. )

Consequence

ESRRB
ENST00000509242.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 0.0320

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: 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

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012386054).

BP6

Variant 14-76499993-G-A is Benign according to our data. Variant chr14-76499993-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44999.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000552 (84/152080) while in subpopulation NFE AF = 0.00101 (69/68004). AF 95% confidence interval is 0.000822. There are 0 homozygotes in GnomAd4. There are 36 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000509242.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESRRB	NM_001379180.1	MANE Select	c.*1535G>A		3_prime_UTR	Exon 7 of 7	NP_001366109.1
ESRRB	NM_004452.4		c.1427G>A	p.Arg476His	missense	Exon 10 of 11	NP_004443.3
ESRRB	NM_001411038.1		c.*1535G>A		3_prime_UTR	Exon 7 of 7	NP_001397967.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESRRB	ENST00000509242.5	TSL:1	c.1427G>A	p.Arg476His	missense	Exon 8 of 9	ENSP00000422488.1
ESRRB	ENST00000505752.6	TSL:1	n.*111G>A		non_coding_transcript_exon	Exon 11 of 12	ENSP00000423004.1
ESRRB	ENST00000644823.1	MANE Select	c.*1535G>A		3_prime_UTR	Exon 7 of 7	ENSP00000493776.1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00101

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000457

AC:

AN:

196962

AF XY:

0.000345

show subpopulations

Gnomad AFR exome

AF:

0.0000848

Gnomad AMR exome

AF:

0.000251

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000856

Gnomad OTH exome

AF:

0.000190

GnomAD4 exome

AF:

0.000804

AC:

1150

AN:

1430086

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

533

AN XY:

707938

show subpopulations

African (AFR)

AF:

0.000182

AC:

AN:

32952

American (AMR)

AF:

0.000307

AC:

AN:

39078

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

38536

South Asian (SAS)

AF:

0.000403

AC:

AN:

81818

European-Finnish (FIN)

AF:

0.0000387

AC:

AN:

51732

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.000969

AC:

1061

AN:

1095358

Other (OTH)

AF:

0.000589

AC:

AN:

59406

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

133

199

266

332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

126

168

210

<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:

0.000552

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.000485

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41406

American (AMR)

AF:

0.000262

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00101

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000722

Hom.:

Bravo

AF:

0.000559

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.000417

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Autosomal recessive nonsyndromic hearing loss 35 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.29

CADD

Benign

2.8

(source)

DANN

Benign

0.87

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0010

LIST_S2

Benign

0.29

M_CAP

Benign

0.022

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.40

MutationAssessor

Benign

-0.34

PhyloP100

0.032

PrimateAI

Benign

0.20

PROVEAN

Benign

0.23

REVEL

Uncertain

0.38

Sift

Benign

0.29

Sift4G

Benign

0.16

Vest4

0.12

MVP

0.48

MPC

0.48

ClinPred

0.0071

GERP RS

-3.2

gMVP

0.063

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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ENST00000509242.5:c.1427G>A

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over