Genetic Variant ESRRA:p.Pro116Pro (chr11-64313973-G-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_004451.5(ESRRA):c.348G>C(p.Pro116Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,579,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

ESRRA
NM_004451.5 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.171

Publications

21 publications found

Variant links:

Genes affected

ESRRA (HGNC:3471): (estrogen related receptor alpha) The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1. [provided by RefSeq, Jun 2019]

ESRRA links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.49).

BP7

Synonymous conserved (PhyloP=-0.171 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004451.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESRRA	NM_004451.5	MANE Select	c.348G>C	p.Pro116Pro	synonymous	Exon 3 of 7	NP_004442.3
ESRRA	NM_001282450.2		c.348G>C	p.Pro116Pro	synonymous	Exon 3 of 7	NP_001269379.1
ESRRA	NM_001282451.2		c.348G>C	p.Pro116Pro	synonymous	Exon 3 of 7	NP_001269380.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESRRA	ENST00000000442.11	TSL:1 MANE Select	c.348G>C	p.Pro116Pro	synonymous	Exon 3 of 7	ENSP00000000442.6
ESRRA	ENST00000406310.6	TSL:1	c.600G>C	p.Pro200Pro	synonymous	Exon 3 of 7	ENSP00000385971.2
ESRRA	ENST00000405666.5	TSL:1	c.348G>C	p.Pro116Pro	synonymous	Exon 3 of 7	ENSP00000384851.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.01e-7

AC:

AN:

1427482

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

707000

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32778

American (AMR)

AF:

0.00

AC:

AN:

39840

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25490

East Asian (EAS)

AF:

0.00

AC:

AN:

38060

South Asian (SAS)

AF:

0.00

AC:

AN:

82226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50500

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4732

European-Non Finnish (NFE)

AF:

9.13e-7

AC:

AN:

1094894

Other (OTH)

AF:

0.00

AC:

AN:

58962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

616

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

9.6

(source)

DANN

Benign

0.79

PhyloP100

-0.17

PromoterAI

0.27

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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