Genetic Variant NM_004451.5:c.743-36C>T (chr11-64314965-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.743-36C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 1,594,400 control chromosomes in the GnomAD database, including 747,017 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 0.87 ( 60175 hom., cov: 34)

Exomes 𝑓: 0.97 ( 686842 hom. )

Consequence

ESRRA
NM_004451.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0350

Publications

9 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=-0.85).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESRRA	NM_004451.5 link	c.743-36C>T		intron_variant	Intron 5 of 6	ENST00000000442.11	NP_004442.3	P11474-1Q569H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESRRA	ENST00000000442.11 link	c.743-36C>T		intron_variant	Intron 5 of 6	1	NM_004451.5	ENSP00000000442.6		P11474-1

Frequencies

GnomAD3 genomes

AF:

0.871

AC:

132539

AN:

152182

Hom.:

60155

Cov.:

show subpopulations

Gnomad AFR

AF:

0.589

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.946

Gnomad ASJ

AF:

0.994

Gnomad EAS

AF:

0.914

Gnomad SAS

AF:

0.804

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.997

Gnomad OTH

AF:

0.905

GnomAD2 exomes

AF:

0.940

AC:

210042

AN:

223508

AF XY:

0.939

show subpopulations

Gnomad AFR exome

AF:

0.584

Gnomad AMR exome

AF:

0.976

Gnomad ASJ exome

AF:

0.994

Gnomad EAS exome

AF:

0.924

Gnomad FIN exome

AF:

0.999

Gnomad NFE exome

AF:

0.997

Gnomad OTH exome

AF:

0.965

GnomAD4 exome

AF:

0.973

AC:

1402878

AN:

1442100

Hom.:

686842

Cov.:

AF XY:

0.969

AC XY:

693928

AN XY:

715836

show subpopulations

African (AFR)

AF:

0.572

AC:

18833

AN:

32926

American (AMR)

AF:

0.974

AC:

41581

AN:

42708

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

25524

AN:

25670

East Asian (EAS)

AF:

0.903

AC:

35024

AN:

38806

South Asian (SAS)

AF:

0.817

AC:

69266

AN:

84750

European-Finnish (FIN)

AF:

1.00

AC:

50107

AN:

50128

Middle Eastern (MID)

AF:

0.972

AC:

4969

AN:

5114

European-Non Finnish (NFE)

AF:

0.998

AC:

1100744

AN:

1102436

Other (OTH)

AF:

0.954

AC:

56830

AN:

59562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

1689

3377

5066

6754

8443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21524

43048

64572

86096

107620

<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:

0.871

AC:

132607

AN:

152300

Hom.:

60175

Cov.:

AF XY:

0.873

AC XY:

65001

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.589

AC:

24466

AN:

41530

American (AMR)

AF:

0.946

AC:

14485

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.994

AC:

3450

AN:

3472

East Asian (EAS)

AF:

0.914

AC:

4736

AN:

5184

South Asian (SAS)

AF:

0.805

AC:

3892

AN:

4832

European-Finnish (FIN)

AF:

1.00

AC:

10627

AN:

10630

Middle Eastern (MID)

AF:

0.969

AC:

285

AN:

294

European-Non Finnish (NFE)

AF:

0.997

AC:

67843

AN:

68028

Other (OTH)

AF:

0.906

AC:

1911

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

635

1270

1904

2539

3174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

874

1748

2622

3496

4370

<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:

0.932

Hom.:

20946

Bravo

AF:

0.859

Asia WGS

AF:

0.850

AC:

2958

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

1.7

(source)

DANN

Benign

0.70

PhyloP100

0.035

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over