14-76462576-C-G

Variant names:

• chr14-76462576-C-G
• rs370878277
• NM_001379180.1:c.492C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001379180.1(ESRRB):​c.492C>G​(p.Asn164Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. N164N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ESRRB NM_001379180.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.469
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.492C>G	p.Asn164Lys	missense	Exon 3 of 7	NP_001366109.1
	ESRRB	NM_004452.4		c.429C>G	p.Asn143Lys	missense	Exon 5 of 11	NP_004443.3
	ESRRB	NM_001411038.1		c.444C>G	p.Asn148Lys	missense	Exon 3 of 7	NP_001397967.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESRRB	ENST00000644823.1	MANE Select	c.492C>G	p.Asn164Lys	missense	Exon 3 of 7	ENSP00000493776.1
	ESRRB	ENST00000509242.5	TSL:1	c.429C>G	p.Asn143Lys	missense	Exon 3 of 9	ENSP00000422488.1
	ESRRB	ENST00000505752.6	TSL:1	n.429C>G		non_coding_transcript_exon	Exon 5 of 12	ENSP00000423004.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111964

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.1	L
PhyloP100		-0.47
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.68	P
Vest4		0.71
MutPred		0.57		Gain of methylation at N148 (P = 6e-04)
MVP		0.87
MPC		1.1
ClinPred		0.99	D
GERP RS		-3.0
gMVP		0.77
Mutation Taster		=18/82	disease causing

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: rs370878277; hg19: chr14-76928919;