rs727504577

Variant names:

• chr14-76498360-ACGGCC-A
• rs727504577
• NM_001379180.1:c.1268_1272delCGGCC

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001379180.1(ESRRB):​c.1268_1272delCGGCC​(p.Thr423SerfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESRRB NM_001379180.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0
• 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 6 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 0.0711 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-76498360-ACGGCC-A is Pathogenic according to our data. Variant chr14-76498360-ACGGCC-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 178970.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.1268_1272delCGGCC	p.Thr423SerfsTer9	frameshift	Exon 7 of 7	NP_001366109.1
	ESRRB	NM_004452.4		c.1205_1209delCGGCC	p.Thr402SerfsTer9	frameshift	Exon 9 of 11	NP_004443.3
	ESRRB	NM_001411038.1		c.1220_1224delCGGCC	p.Thr407SerfsTer9	frameshift	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.1268_1272delCGGCC	p.Thr423SerfsTer9	frameshift	Exon 7 of 7	ENSP00000493776.1
	ESRRB	ENST00000509242.5	TSL:1	c.1205_1209delCGGCC	p.Thr402SerfsTer9	frameshift	Exon 7 of 9	ENSP00000422488.1
	ESRRB	ENST00000505752.6	TSL:1	n.1205_1209delCGGCC		non_coding_transcript_exon	Exon 9 of 12	ENSP00000423004.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs727504577; hg19: chr14-76964703;