NM_001379180.1:c.1224G>A

Variant names:

• chr14-76498317-G-A
• rs727503041
• NM_001379180.1:c.1224G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001379180.1(ESRRB):​c.1224G>A​(p.Trp408*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESRRB NM_001379180.1 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.64
• Publications: 0 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: PanelApp Australia, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000259124 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.103 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-76498317-G-A is Pathogenic according to our data. Variant chr14-76498317-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 163423.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	NM_001379180.1	MANE Select	c.1224G>A	p.Trp408*	stop_gained	Exon 7 of 7	NP_001366109.1
	ESRRB	NM_004452.4		c.1161G>A	p.Trp387*	stop_gained	Exon 9 of 11	NP_004443.3
	ESRRB	NM_001411038.1		c.1176G>A	p.Trp392*	stop_gained	Exon 7 of 7	NP_001397967.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	ENST00000644823.1	MANE Select	c.1224G>A	p.Trp408*	stop_gained	Exon 7 of 7	ENSP00000493776.1
	ESRRB	ENST00000509242.5	TSL:1	c.1161G>A	p.Trp387*	stop_gained	Exon 7 of 9	ENSP00000422488.1
	ESRRB	ENST00000505752.6	TSL:1	n.1161G>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000423004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Jun 02, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Trp387X variant in ESRRB has not been reported in individuals with hearing l oss. This nonsense variant leads to a premature termination codon at position 38 7, which is predicted to lead to a truncated or absent protein. To date, only on e truncating variant in ESRRB has been reported as disease causing in a hearing loss family (Collin 2008). Therefore, although truncating variants are suggested to be pathogenic, additional data is needed to confirm this. In summary, this v ariant is likely pathogenic, though additional studies are required to fully est ablish its clinical significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		4.6
Vest4		0.87
GERP RS		4.5
Mutation Taster		=13/187	disease causing (ClinVar)

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: rs727503041; hg19: chr14-76964660;