rs146351534

Positions:

• chr14-76498393-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 14/18 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.85

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.1300G>A	p.Val434Ile	missense_variant	7/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.1300G>A	p.Val434Ile	missense_variant	7/7		NM_001379180.1	P1
	ENST00000554926.1	n.415-2813C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1637 AN: 152226 Hom.: 14 Cov.: 32

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

GnomAD3 exomes AF: 0.0115 AC: 2872 AN: 249282 Hom.: 43 AF XY: 0.0116 AC XY: 1569 AN XY: 135276

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 SAS exome AF: 0.000981

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.: 35 AF XY: 0.0128 AC XY: 9328 AN XY: 726866

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.0115

Gnomad4 ASJ exome AF: 0.00670

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000904

Gnomad4 FIN exome AF: 0.0163

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0109

GnomAD4 genome AF: 0.0107 AC: 1637 AN: 152344 Hom.: 14 Cov.: 32 AF XY: 0.0108 AC XY: 803 AN XY: 74494

Gnomad4 AFR AF: 0.00236

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0146 Hom.: 28

Bravo AF: 0.0102

TwinsUK AF: 0.0175 AC: 65

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.0110 AC: 1336

EpiCase AF: 0.0216

EpiControl AF: 0.0200

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	ESRRB: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2019	This variant is associated with the following publications: (PMID: 22951369, 29636544) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 30, 2012

Val413Ile in Exon 09 of ESRRB: This variant is not expected to have clinical sig nificance because it has been identified in 1.3% (91/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs146351534). -

Autosomal recessive nonsyndromic hearing loss 35 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.87
DEOGEN2	Benign	0.28	T;.;.;.
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T;.;T;T
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.73	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.11	N;N;.;N
REVEL	Benign	0.071
Sift	Benign	0.92	T;T;.;T
Polyphen		0.016	B;.;.;.
Vest4		0.061, 0.060
MPC		0.32
ClinPred		0.0072	T
GERP RS		-5.7
gMVP		0.054

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

Other links and lift over

dbSNP: rs146351534; hg19: chr14-76964736; COSMIC: COSV55065767; COSMIC: COSV55065767;