14-76439390-G-T

Variant names:

• chr14-76439390-G-T
• rs773933130
• NM_001379180.1:c.100G>T

Variant summary

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

The NM_001379180.1(ESRRB):​c.100G>T​(p.Gly34Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G34S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESRRB NM_001379180.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.04
• Publications: 1 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRB	NM_001379180.1	c.100G>T	p.Gly34Cys	missense_variant	Exon 2 of 7	ENST00000644823.1	NP_001366109.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRB	ENST00000644823.1	c.100G>T	p.Gly34Cys	missense_variant	Exon 2 of 7		NM_001379180.1	ENSP00000493776.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T;.;.;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;.;D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Uncertain	2.0	.;M;.;M
PhyloP100		8.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.4	N;N;.;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	D;D;.;D
Sift4G	Uncertain	0.016	.;D;.;D
Polyphen		1.0	D;.;.;.
Vest4		0.86, 0.86
MutPred		0.22		Loss of phosphorylation at S19 (P = 0.0842);.;.;.;
MVP		0.79
MPC		1.2
ClinPred		0.97	D
GERP RS		4.0
PromoterAI		0.028	Neutral
gMVP		0.62
Mutation Taster		=49/51	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: rs773933130; hg19: chr14-76905733;