rs1555344820

chr14-76491603-C-CG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001379180.1(ESRRB):c.1011dup(p.Leu338AlafsTer68) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ESRRB NM_001379180.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -3.34

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-76491603-C-CG is Pathogenic according to our data. Variant chr14-76491603-C-CG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 505350.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESRRB	NM_001379180.1	c.1011dup	p.Leu338AlafsTer68	frameshift_variant	6/7	ENST00000644823.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESRRB	ENST00000644823.1	c.1011dup	p.Leu338AlafsTer68	frameshift_variant	6/7		NM_001379180.1	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 18, 2016

The p.Leu317fs variant in ESRRB has not been previously reported in individuals with hearing loss or large population studies. This frameshift variant is predic ted to alter the protein?s amino acid sequence beginning at position 317 and lea d to a premature termination codon 68 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Truncating variants in ESRRB have been associated with autosomal recessive sensorineural hearing loss; however, the exact mechanism of disease has not yet been established. In summar y, although additional studies are required to fully establish its clinical sign ificance, the p.Leu317fs variant is likely pathogenic for autosomal recessive he aring loss. -

Computational scores

Source: dbNSFP v4.3

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: rs1555344820; hg19: chr14-76957946;