rs886050806

Variant names:

• chr14-76482097-T-C
• rs886050806
• NM_001379180.1:c.659T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001379180.1(ESRRB):​c.659T>C​(p.Leu220Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ESRRB NM_001379180.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.10
• Publications: 1 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14449152).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379180.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	NM_001379180.1	MANE Select	c.659T>C	p.Leu220Ser	missense	Exon 4 of 7	NP_001366109.1	A0A2R8Y491
	ESRRB	NM_004452.4		c.596T>C	p.Leu199Ser	missense	Exon 6 of 11	NP_004443.3
	ESRRB	NM_001411038.1		c.611T>C	p.Leu204Ser	missense	Exon 4 of 7	NP_001397967.1	E7EWD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	ENST00000644823.1	MANE Select	c.659T>C	p.Leu220Ser	missense	Exon 4 of 7	ENSP00000493776.1	A0A2R8Y491
	ESRRB	ENST00000509242.5	TSL:1	c.596T>C	p.Leu199Ser	missense	Exon 4 of 9	ENSP00000422488.1	O95718-1
	ESRRB	ENST00000505752.6	TSL:1	n.596T>C		non_coding_transcript_exon	Exon 6 of 12	ENSP00000423004.1	O95718-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive nonsyndromic hearing loss 35 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.0099	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.060
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N
PhyloP100		5.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.16
Sift	Benign	0.47	T
Sift4G	Benign	0.92	T
Polyphen		0.013	B
Vest4		0.60
MutPred		0.28		Gain of phosphorylation at L204 (P = 0.0191)
MVP		0.71
MPC		0.55
ClinPred		0.48	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.81
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs886050806; hg19: chr14-76948440; COSMIC: COSV107224686;