rs727504577

Positions:

• chr14-76498360-ACGGCC-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001379180.1(ESRRB):​c.1268_1272del​(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

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]

(HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 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 1 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 id is 178970.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-76498360-ACGGCC-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.1268_1272del	p.Thr423SerfsTer9	frameshift_variant	7/7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1	c.1268_1272del	p.Thr423SerfsTer9	frameshift_variant	7/7		NM_001379180.1	ENSP00000493776	P1
	ENST00000554926.1	n.415-2785_415-2781del		intron_variant, non_coding_transcript_variant		3

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

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

Jun 02, 2013

The Thr402fs variant in ESRRB has not been previously reported in individuals wi th hearing loss. This frameshift variant is predicted to alter the protein?s ami no acid sequence beginning at position 402 and lead to a premature termination c odon 9 amino acids downstream. This alteration is then predicted to lead to a tr uncated or absent protein. Loss of function variants in ESRRB have been associat ed with autosomal recessive sensorineural hearing loss, however the exact mechan ism of disease has not yet been established. In summary, this variant is likely to be pathogenic, though additional studies are required to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504577; hg19: chr14-76964703;