Genetic Variant ESRRA:c.1012+65C>T (chr11-64315335-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004451.5(ESRRA):c.1012+65C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 1,476,794 control chromosomes in the GnomAD database, including 17,438 homozygotes. 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 0.12 ( 1390 hom., cov: 34)

Exomes 𝑓: 0.15 ( 16048 hom. )

Consequence

ESRRA
NM_004451.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.252

Publications

29 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

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	Effect	Exon Rank	Protein
ESRRA	NM_004451.5	MANE Select	c.1012+65C>T	intron	N/A	NP_004442.3
ESRRA	NM_001282450.2		c.1012+65C>T	intron	N/A	NP_001269379.1
ESRRA	NM_001282451.2		c.1009+65C>T	intron	N/A	NP_001269380.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ESRRA	ENST00000000442.11	TSL:1 MANE Select	c.1012+65C>T	intron	N/A	ENSP00000000442.6
ESRRA	ENST00000406310.6	TSL:1	c.1261+65C>T	intron	N/A	ENSP00000385971.2
ESRRA	ENST00000405666.5	TSL:1	c.1012+65C>T	intron	N/A	ENSP00000384851.1

Frequencies

GnomAD3 genomes

AF:

0.120

AC:

18217

AN:

152154

Hom.:

1391

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0430

Gnomad AMI

AF:

0.106

Gnomad AMR

AF:

0.129

Gnomad ASJ

AF:

0.117

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.0714

Gnomad FIN

AF:

0.163

Gnomad MID

AF:

0.158

Gnomad NFE

AF:

0.161

Gnomad OTH

AF:

0.151

GnomAD4 exome

AF:

0.153

AC:

202279

AN:

1324522

Hom.:

16048

AF XY:

0.152

AC XY:

98547

AN XY:

647694

show subpopulations

African (AFR)

AF:

0.0363

AC:

1074

AN:

29556

American (AMR)

AF:

0.114

AC:

2957

AN:

26040

Ashkenazi Jewish (ASJ)

AF:

0.127

AC:

2452

AN:

19324

East Asian (EAS)

AF:

0.104

AC:

3967

AN:

38044

South Asian (SAS)

AF:

0.0850

AC:

5741

AN:

67564

European-Finnish (FIN)

AF:

0.159

AC:

7539

AN:

47422

Middle Eastern (MID)

AF:

0.181

AC:

937

AN:

5176

European-Non Finnish (NFE)

AF:

0.163

AC:

169220

AN:

1036590

Other (OTH)

AF:

0.153

AC:

8392

AN:

54806

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

8610

17221

25831

34442

43052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6110

12220

18330

24440

30550

<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:

0.120

AC:

18220

AN:

152272

Hom.:

1390

Cov.:

AF XY:

0.119

AC XY:

8884

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0429

AC:

1783

AN:

41570

American (AMR)

AF:

0.129

AC:

1975

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

405

AN:

3472

East Asian (EAS)

AF:

0.110

AC:

571

AN:

5176

South Asian (SAS)

AF:

0.0718

AC:

347

AN:

4830

European-Finnish (FIN)

AF:

0.163

AC:

1730

AN:

10602

Middle Eastern (MID)

AF:

0.163

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10935

AN:

68006

Other (OTH)

AF:

0.156

AC:

329

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

820

1640

2460

3280

4100

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

202

404

606

808

1010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.146

Hom.:

5554

Bravo

AF:

0.115

Asia WGS

AF:

0.116

AC:

401

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

2.1

(source)

DANN

Benign

0.73

PhyloP100

-0.25

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over