14-76439369-A-G

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.79A>G(p.Arg27Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00134 in 1,613,686 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (37 hom.)
• Consequence: ESRRB NM_001379180.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.05

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00788784).
• BP6: Variant 14-76439369-A-G is Benign according to our data. Variant chr14-76439369-A-G is described in ClinVar as [Benign]. Clinvar id is 163416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-76439369-A-G is described in Lovd as [Likely_benign]. Variant chr14-76439369-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00162 (247/152334) while in subpopulation EAS AF= 0.0416 (215/5164). AF 95% confidence interval is 0.0371. There are 7 homozygotes in gnomad4. There are 123 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.79A>G	p.Arg27Gly	missense_variant	2/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.79A>G	p.Arg27Gly	missense_variant	2/7		NM_001379180.1	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152216 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0417

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00317 AC: 782 AN: 246644 Hom.: 11 AF XY: 0.00289 AC XY: 389 AN XY: 134448

Gnomad AFR exome AF: 0.000660

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0416

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00131 AC: 1909 AN: 1461352 Hom.: 37 Cov.: 36 AF XY: 0.00128 AC XY: 928 AN XY: 726994

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0420

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00296

GnomAD4 genome AF: 0.00162 AC: 247 AN: 152334 Hom.: 7 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74490

Gnomad4 AFR AF: 0.000288

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0416

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00166 Hom.: 6

Bravo AF: 0.00190

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00319 AC: 387

Asia WGS AF: 0.0160 AC: 57 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 16, 2013	Arg6Gly in exon 4 of ESRRB: This variant is not expected to have clinical signif icance because it has been identified in 1.7% (10/572) of Asian chromosomes by t he 1000 Genomes Project (dbSNP rs143477571) -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 35 Benign:1

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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.95	D;.;D;D
MetaRNN	Benign	0.0079	T;T;T;T
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.2	N;N;.;N
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0020	D;D;.;D
Polyphen		0.97	D;.;.;.
Vest4		0.71
MVP		0.86
MPC		1.4
ClinPred		0.061	T
GERP RS		3.0
gMVP		0.63

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: rs143477571; hg19: chr14-76905712; COSMIC: COSV99834657; COSMIC: COSV99834657;