Genetic Variant ENST00000473497.5:n.74-16429C>T (chr6-151685446-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 ENST00000473497.5(ESR1):n.74-16429C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 151,926 control chromosomes in the GnomAD database, including 13,776 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 0.42 ( 13776 hom., cov: 32)

Consequence

ESR1
ENST00000473497.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.703

Publications

6 publications found

Variant links:

Genes affected

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ESR1 Gene-Disease associations (from GenCC):

estrogen resistance syndrome
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ESR1 links:

ENSG00000294140 (HGNC:):

ENSG00000294140 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=-0.74).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.469 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
ESR1	NM_001385568.1 link	c.-201-16429C>T	intron_variant	Intron 1 of 9	NP_001372497.1
ESR1	XM_017010377.2 link	c.-201-16429C>T	intron_variant	Intron 2 of 10	XP_016865866.1	P03372-1G4XH65
ESR1	XM_017010380.2 link	c.-71+28683C>T	intron_variant	Intron 1 of 8	XP_016865869.1	P03372-1G4XH65
ESR1	XM_047418290.1 link	c.-201-16429C>T	intron_variant	Intron 1 of 9	XP_047274246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000473497.5 link	n.74-16429C>T		intron_variant	Intron 1 of 2	1
ENSG00000294140	ENST00000721398.1 link	n.86-2143C>T		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes

AF:

0.418

AC:

63411

AN:

151808

Hom.:

13771

Cov.:

show subpopulations

Gnomad AFR

AF:

0.348

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.376

Gnomad ASJ

AF:

0.543

Gnomad EAS

AF:

0.114

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.494

Gnomad MID

AF:

0.437

Gnomad NFE

AF:

0.473

Gnomad OTH

AF:

0.406

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.418

AC:

63457

AN:

151926

Hom.:

13776

Cov.:

AF XY:

0.413

AC XY:

30693

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.348

AC:

14404

AN:

41420

American (AMR)

AF:

0.375

AC:

5732

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.543

AC:

1882

AN:

3468

East Asian (EAS)

AF:

0.115

AC:

592

AN:

5160

South Asian (SAS)

AF:

0.431

AC:

2076

AN:

4818

European-Finnish (FIN)

AF:

0.494

AC:

5206

AN:

10548

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.473

AC:

32135

AN:

67932

Other (OTH)

AF:

0.407

AC:

858

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1929

3857

5786

7714

9643

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

612

1224

1836

2448

3060

<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:

0.455

Hom.:

25500

Bravo

AF:

0.405

Asia WGS

AF:

0.323

AC:

1124

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.6

(source)

DANN

Benign

0.90

PhyloP100

-0.70

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over