dbSNP rs3020331: ESR1:n.74-14230C>T (chr6-151687645-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4BA1

The ENST00000473497.5(ESR1):n.74-14230C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.379 in 151,968 control chromosomes in the GnomAD database, including 11,388 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 0.38 ( 11388 hom., cov: 32)

Consequence

ESR1
ENST00000473497.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.85

Publications

27 publications found

Variant links:

COSMIC-nc: COSV68604072

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.13).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	Protein	UniProt
ESR1	NM_001385568.1 link	c.-201-14230C>T	intron_variant	Intron 1 of 9	NP_001372497.1
ESR1	XM_017010377.2 link	c.-201-14230C>T	intron_variant	Intron 2 of 10	XP_016865866.1	P03372-1G4XH65
ESR1	XM_017010380.2 link	c.-71+30882C>T	intron_variant	Intron 1 of 8	XP_016865869.1	P03372-1G4XH65
ESR1	XM_047418290.1 link	c.-201-14230C>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.74-14230C>T		intron_variant	Intron 1 of 2	1
ENSG00000294140	ENST00000721398.1 link	n.142C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.379

AC:

57531

AN:

151850

Hom.:

11387

Cov.:

show subpopulations

Gnomad AFR

AF:

0.316

Gnomad AMI

AF:

0.556

Gnomad AMR

AF:

0.362

Gnomad ASJ

AF:

0.367

Gnomad EAS

AF:

0.136

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.486

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.433

Gnomad OTH

AF:

0.353

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

GnomAD4 genome

AF:

0.379

AC:

57557

AN:

151968

Hom.:

11388

Cov.:

AF XY:

0.376

AC XY:

27913

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.316

AC:

13105

AN:

41426

American (AMR)

AF:

0.363

AC:

5539

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

1272

AN:

3468

East Asian (EAS)

AF:

0.136

AC:

703

AN:

5168

South Asian (SAS)

AF:

0.223

AC:

1073

AN:

4812

European-Finnish (FIN)

AF:

0.486

AC:

5124

AN:

10538

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.433

AC:

29402

AN:

67968

Other (OTH)

AF:

0.349

AC:

736

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1769

3538

5306

7075

8844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

550

1100

1650

2200

2750

<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:

0.408

Hom.:

44399

Bravo

AF:

0.365

Asia WGS

AF:

0.187

AC:

655

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

1.8

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