dbSNP rs201726554: ESRRB:p.Pro470Leu (chr14-76499975-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_004452.4(ESRRB):c.1409C>T(p.Pro470Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,600,692 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00081 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00096 ( 6 hom. )

Consequence

ESRRB
NM_004452.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B: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: 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

new If you want to explore the variant's impact on the transcript NM_004452.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043939054).

BP6

Variant 14-76499975-C-T is Benign according to our data. Variant chr14-76499975-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 163424.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000808 (123/152272) while in subpopulation SAS AF = 0.00456 (22/4826). AF 95% confidence interval is 0.00309. There are 1 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004452.4. 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.*1517C>T		3_prime_UTR	Exon 7 of 7	NP_001366109.1	A0A2R8Y491
ESRRB	NM_004452.4		c.1409C>T	p.Pro470Leu	missense	Exon 10 of 11	NP_004443.3
ESRRB	NM_001411038.1		c.*1517C>T		3_prime_UTR	Exon 7 of 7	NP_001397967.1	E7EWD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRRB	ENST00000509242.5	TSL:1	c.1409C>T	p.Pro470Leu	missense	Exon 8 of 9	ENSP00000422488.1	O95718-1
ESRRB	ENST00000644823.1	MANE Select	c.*1517C>T		3_prime_UTR	Exon 7 of 7	ENSP00000493776.1	A0A2R8Y491
ESRRB	ENST00000505752.6	TSL:1	n.*93C>T		non_coding_transcript_exon	Exon 11 of 12	ENSP00000423004.1	O95718-2

Frequencies

GnomAD3 genomes

AF:

0.000808

AC:

123

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.0104

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00455

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00132

AC:

295

AN:

223360

AF XY:

0.00152

show subpopulations

Gnomad AFR exome

AF:

0.0000732

Gnomad AMR exome

AF:

0.000480

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.000240

Gnomad FIN exome

AF:

0.0000490

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.000708

GnomAD4 exome

AF:

0.000957

AC:

1386

AN:

1448420

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

768

AN XY:

718748

show subpopulations

African (AFR)

AF:

0.000150

AC:

AN:

33308

American (AMR)

AF:

0.000306

AC:

AN:

42434

Ashkenazi Jewish (ASJ)

AF:

0.0113

AC:

291

AN:

25774

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39348

South Asian (SAS)

AF:

0.00455

AC:

381

AN:

83738

European-Finnish (FIN)

AF:

0.0000570

AC:

AN:

52662

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000531

AC:

587

AN:

1105332

Other (OTH)

AF:

0.00155

AC:

AN:

60068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

174

262

349

436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.000808

AC:

123

AN:

152272

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41540

American (AMR)

AF:

0.00144

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0104

AC:

AN:

3468

East Asian (EAS)

AF:

0.000387

AC:

AN:

5170

South Asian (SAS)

AF:

0.00456

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000799

Hom.:

Bravo

AF:

0.000865

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Autosomal recessive nonsyndromic hearing loss 35 (1)

ESRRB-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.31

CADD

Benign

5.1

(source)

DANN

Uncertain

0.98

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.43

M_CAP

Benign

0.014

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.43

MutationAssessor

Benign

0.34

PhyloP100

0.032

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.060

REVEL

Benign

0.13

Sift

Uncertain

0.0050

Sift4G

Benign

0.23

gMVP

0.10

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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