Genetic Variant NM_000125.4:c.30T>C (chr6-151807942-T-C) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000125.4(ESR1):c.30T>C(p.Ser10Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,613,166 control chromosomes in the GnomAD database, including 182,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17171 hom., cov: 33)

Exomes 𝑓: 0.47 ( 165449 hom. )

Consequence

ESR1
NM_000125.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.664

Publications

167 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 6-151807942-T-C is Benign according to our data. Variant chr6-151807942-T-C is described in ClinVar as Benign. ClinVar VariationId is 1250979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.664 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESR1	NM_000125.4	MANE Select	c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 8	NP_000116.2
ESR1	NM_001291230.2		c.30T>C	p.Ser10Ser	synonymous	Exon 2 of 9	NP_001278159.1
ESR1	NM_001122740.2		c.30T>C	p.Ser10Ser	synonymous	Exon 2 of 9	NP_001116212.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ESR1	ENST00000206249.8	TSL:1 MANE Select	c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 8	ENSP00000206249.3
ESR1	ENST00000406599.5	TSL:1	c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 4	ENSP00000384064.1
ESR1	ENST00000456483.3	TSL:1	c.30T>C	p.Ser10Ser	synonymous	Exon 1 of 5	ENSP00000415934.3

Frequencies

GnomAD3 genomes

AF:

0.475

AC:

72099

AN:

151918

Hom.:

17166

Cov.:

show subpopulations

Gnomad AFR

AF:

0.489

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.469

Gnomad ASJ

AF:

0.511

Gnomad EAS

AF:

0.382

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.421

Gnomad MID

AF:

0.456

Gnomad NFE

AF:

0.480

Gnomad OTH

AF:

0.463

GnomAD2 exomes

AF:

0.463

AC:

114483

AN:

247438

AF XY:

0.465

show subpopulations

Gnomad AFR exome

AF:

0.491

Gnomad AMR exome

AF:

0.447

Gnomad ASJ exome

AF:

0.510

Gnomad EAS exome

AF:

0.364

Gnomad FIN exome

AF:

0.419

Gnomad NFE exome

AF:

0.476

Gnomad OTH exome

AF:

0.465

GnomAD4 exome

AF:

0.475

AC:

693862

AN:

1461130

Hom.:

165449

Cov.:

AF XY:

0.475

AC XY:

345476

AN XY:

726860

show subpopulations

African (AFR)

AF:

0.489

AC:

16372

AN:

33466

American (AMR)

AF:

0.450

AC:

20095

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.509

AC:

13309

AN:

26128

East Asian (EAS)

AF:

0.390

AC:

15493

AN:

39676

South Asian (SAS)

AF:

0.486

AC:

41935

AN:

86216

European-Finnish (FIN)

AF:

0.425

AC:

22631

AN:

53224

Middle Eastern (MID)

AF:

0.480

AC:

2766

AN:

5768

European-Non Finnish (NFE)

AF:

0.479

AC:

532245

AN:

1111628

Other (OTH)

AF:

0.481

AC:

29016

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

22657

45314

67972

90629

113286

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15772

31544

47316

63088

78860

<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:

0.474

AC:

72129

AN:

152036

Hom.:

17171

Cov.:

AF XY:

0.472

AC XY:

35058

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.489

AC:

20278

AN:

41484

American (AMR)

AF:

0.469

AC:

7164

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.511

AC:

1773

AN:

3470

East Asian (EAS)

AF:

0.382

AC:

1954

AN:

5116

South Asian (SAS)

AF:

0.498

AC:

2402

AN:

4824

European-Finnish (FIN)

AF:

0.421

AC:

4448

AN:

10570

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.480

AC:

32606

AN:

67976

Other (OTH)

AF:

0.464

AC:

980

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

2026

4052

6079

8105

10131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

648

1296

1944

2592

3240

<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:

0.473

Hom.:

40001

Bravo

AF:

0.472

Asia WGS

AF:

0.445

AC:

1548

AN:

3478

EpiCase

AF:

0.477

EpiControl

AF:

0.476

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial cancer of breast;C1832662:Myocardial infarction, susceptibility to;C3809250:Estrogen resistance syndrome;C3887485:Migraine with or without aura, susceptibility to, 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

7.2

(source)

DANN

Benign

0.49

PhyloP100

-0.66

PromoterAI

0.068

Neutral

(source)

Mutation Taster

=99/1

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