Genetic Variant ENST00000509242.5:c.3G>A (chr14-76439356-G-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The ENST00000509242.5(ESRRB):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ESRRB
ENST00000509242.5 start_lost

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 9.91

Publications

0 publications found

Variant links:

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

ESRRB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 61 codons. Genomic position: 76439534. Lost 0.119 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000509242.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRRB	NM_001379180.1	MANE Select	c.66G>A	p.Met22Ile	missense	Exon 2 of 7	NP_001366109.1	A0A2R8Y491
ESRRB	NM_004452.4		c.3G>A	p.Met1?	start_lost	Exon 4 of 11	NP_004443.3
ESRRB	NM_001411038.1		c.18G>A	p.Met6Ile	missense	Exon 2 of 7	NP_001397967.1	E7EWD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ESRRB	ENST00000509242.5	TSL:1	c.3G>A	p.Met1?	start_lost	Exon 2 of 9	ENSP00000422488.1	O95718-1
ESRRB	ENST00000644823.1	MANE Select	c.66G>A	p.Met22Ile	missense	Exon 2 of 7	ENSP00000493776.1	A0A2R8Y491
ESRRB	ENST00000505752.6	TSL:1	n.3G>A		non_coding_transcript_exon	Exon 4 of 12	ENSP00000423004.1	O95718-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461338

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112006

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Premature ovarian insufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.41

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.016

Eigen

Benign

0.099

Eigen_PC

Benign

0.22

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.75

MetaSVM

Uncertain

0.26

PhyloP100

9.9

PROVEAN

Benign

-0.74

REVEL

Uncertain

0.57

Sift

Benign

0.060

Sift4G

Uncertain

0.038

Polyphen

0.011

Vest4

0.90

MutPred

0.26

Loss of stability (P = 0.1342)

MVP

0.98

ClinPred

0.99

GERP RS

4.9

PromoterAI

-0.0060

Neutral

(source)

gMVP

0.49

Mutation Taster

=25/175

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over