6-151949537-C-T

Variant names:

Variant summary

Our verdict is . The variant received -12 classification points (ACMG Germline Pathogenicity v2019): 0P and 12B. BA1BP4_Strong

The NM_000125.4(ESR1):c.1096+5029C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.526 (AC=79,979) in the gnomAD database across 152,148 control chromosomes, including 23,484 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.67. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.53 ( 23484 hom., cov: 33)

Consequence

ESR1
NM_000125.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.268

Publications

85 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: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics, Orphanet

ESR1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000125.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -12 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.6698 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESR1	NM_000125.4	MANE Select	c.1096+5029C>T	intron	N/A	NP_000116.2	P03372-1
ESR1	NM_001291230.2		c.1102+5029C>T	intron	N/A	NP_001278159.1
ESR1	NM_001122740.2		c.1096+5029C>T	intron	N/A	NP_001116212.1	P03372-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1096+5029C>T	intron	N/A	ENSP00000206249.3	P03372-1
ESR1	ENST00000406599.5	TSL:1	c.453-111454C>T	intron	N/A	ENSP00000384064.1	Q9H2M1
ESR1	ENST00000427531.6	TSL:1	c.577+5029C>T	intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79970

AN:

152030

Hom.:

23488

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.713

Gnomad AMR

AF:

0.503

Gnomad ASJ

AF:

0.661

Gnomad EAS

AF:

0.200

Gnomad SAS

AF:

0.405

Gnomad FIN

AF:

0.656

Gnomad MID

AF:

0.696

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.568

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

GnomAD4 genome

AF:

0.526

AC:

79979

AN:

152148

Hom.:

23484

Cov.:

AF XY:

0.521

AC XY:

38758

AN XY:

74374

show subpopulations

African (AFR)

AF:

0.292

AC:

12125

AN:

41506

American (AMR)

AF:

0.503

AC:

7691

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.661

AC:

2294

AN:

3468

East Asian (EAS)

AF:

0.200

AC:

1034

AN:

5178

South Asian (SAS)

AF:

0.407

AC:

1961

AN:

4818

European-Finnish (FIN)

AF:

0.656

AC:

6947

AN:

10592

Middle Eastern (MID)

AF:

0.707

AC:

208

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45884

AN:

67980

Other (OTH)

AF:

0.563

AC:

1186

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1761

3521

5282

7042

8803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

684

1368

2052

2736

3420

<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:

0.617

Hom.:

99477

Bravo

AF:

0.500

Asia WGS

AF:

0.309

AC:

1077

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.222

AC:

27315

AN:

122804

Turkish Variome

AF:

0.599

AC:

926

AN:

1546

Hom.:

276

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.181

AC:

1626

AN:

8960

Hom.:

151

ABraOM SABE-WGS-1171

AF:

0.560

AC:

1312

AN:

2342

Hom.:

382

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.79

(source)

DANN

Benign

0.59

PhyloP100

-0.27

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over