rs200237229

Positions:

• chr14-76499993-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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. 13/18 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.0320

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 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 id is 44999.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=2}. Variant chr14-76499993-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.*1535G>A		3_prime_UTR_variant	7/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.*1535G>A		3_prime_UTR_variant	7/7		NM_001379180.1	P1
	ENST00000554926.1	n.414+2164C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152080 Hom.: 0 Cov.: 33

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

GnomAD3 exomes AF: 0.000457 AC: 90 AN: 196962 Hom.: 1 AF XY: 0.000345 AC XY: 36 AN XY: 104430

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 SAS exome AF: 0.000357

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.: 3 Cov.: 31 AF XY: 0.000753 AC XY: 533 AN XY: 707938

Gnomad4 AFR exome AF: 0.000182

Gnomad4 AMR exome AF: 0.000307

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000403

Gnomad4 FIN exome AF: 0.0000387

Gnomad4 NFE exome AF: 0.000969

Gnomad4 OTH exome AF: 0.000589

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152080 Hom.: 0 Cov.: 33 AF XY: 0.000485 AC XY: 36 AN XY: 74270

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000821 Hom.: 0

Bravo AF: 0.000559

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.000417 AC: 50

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 24, 2017	p.Arg476His in exon 10 of ESRRB: This variant is not expected to have clinical s ignificance because the arginine (Arg) at position 476 is not conserved across m ammals and the change to histidine (His) is present in several species including chimp. In addition, this variant has been identified in 0.1% (81/96870) of Euro pean chromosomes including 1 homozygote by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org/; dbSNP rs200237229). -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	2.8
DANN	Benign	0.87
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0010	N
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.012	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	-0.34	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.23	N;N
REVEL	Uncertain	0.38
Sift	Benign	0.29	T;T
Sift4G	Benign	0.16	T;T
Vest4		0.12
MVP		0.48
MPC		0.48
ClinPred		0.0071	T
GERP RS		-3.2
gMVP		0.063

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200237229; hg19: chr14-76966336; COSMIC: COSV55059313; COSMIC: COSV55059313;