rs1555345959

Variant names:

• chr14-76500696-G-GA
• rs1555345959
• ENST00000509242.5:c.1505dupA

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PVS1_Moderate PM2 BS1_Supporting

The NM_004452.4(ESRRB):​c.1505dupA​(p.His503AlafsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. K502K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ESRRB NM_004452.4 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.518
• 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: 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

ENSG00000259124 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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 0.0138 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00000205 (3/1461576) while in subpopulation MID AF = 0.000347 (2/5768). AF 95% confidence interval is 0.0000609. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004452.4. 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.*2241dupA		3_prime_UTR	Exon 7 of 7	NP_001366109.1	A0A2R8Y491
	ESRRB	NM_004452.4		c.1505dupA	p.His503AlafsTer40	frameshift	Exon 11 of 11	NP_004443.3
	ESRRB	NM_001411038.1		c.*2241dupA		3_prime_UTR	Exon 7 of 7	NP_001397967.1	E7EWD9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	ENST00000509242.5	TSL:1	c.1505dupA	p.His503AlafsTer40	frameshift	Exon 9 of 9	ENSP00000422488.1	O95718-1
	ESRRB	ENST00000644823.1	MANE Select	c.*2241dupA		3_prime_UTR	Exon 7 of 7	ENSP00000493776.1	A0A2R8Y491
	ESRRB	ENST00000505752.6	TSL:1	n.*189dupA		non_coding_transcript_exon	Exon 12 of 12	ENSP00000423004.1	O95718-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461576 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727082

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111818

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52

Splicing

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

Other links and lift over

dbSNP: rs1555345959; hg19: chr14-76967039;