dbSNP rs9341077: ESR1:c.*3027T>C (chr6-152101993-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000125.4(ESR1):c.*3027T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 214,488 control chromosomes in the GnomAD database, including 150 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 0.034 ( 94 hom., cov: 32)

Exomes 𝑓: 0.035 ( 56 hom. )

Consequence

ESR1
NM_000125.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.300

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0339 (5160/152254) while in subpopulation AMR AF= 0.0481 (736/15298). AF 95% confidence interval is 0.0452. There are 94 homozygotes in gnomad4. There are 2464 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 94 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4 link	c.*3027T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000206249.8	NP_000116.2	P03372-1G4XH65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8 link	c.*3027T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_000125.4	ENSP00000206249.3		P03372-1

Frequencies

GnomAD3 genomes

AF:

0.0339

AC:

5155

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0276

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.0483

Gnomad ASJ

AF:

0.0441

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0128

Gnomad FIN

AF:

0.0364

Gnomad MID

AF:

0.0570

Gnomad NFE

AF:

0.0370

Gnomad OTH

AF:

0.0530

GnomAD4 exome

AF:

0.0349

AC:

2170

AN:

62234

Hom.:

Cov.:

AF XY:

0.0358

AC XY:

1035

AN XY:

28902

show subpopulations

Gnomad4 AFR exome

AF:

0.0247

Gnomad4 AMR exome

AF:

0.0394

Gnomad4 ASJ exome

AF:

0.0458

Gnomad4 EAS exome

AF:

0.000217

Gnomad4 SAS exome

AF:

0.00564

Gnomad4 FIN exome

AF:

0.0404

Gnomad4 NFE exome

AF:

0.0420

Gnomad4 OTH exome

AF:

0.0411

GnomAD4 genome

AF:

0.0339

AC:

5160

AN:

152254

Hom.:

Cov.:

AF XY:

0.0331

AC XY:

2464

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0276

Gnomad4 AMR

AF:

0.0481

Gnomad4 ASJ

AF:

0.0441

Gnomad4 EAS

AF:

0.000965

Gnomad4 SAS

AF:

0.0131

Gnomad4 FIN

AF:

0.0364

Gnomad4 NFE

AF:

0.0370

Gnomad4 OTH

AF:

0.0529

Alfa

AF:

0.0353

Hom.:

Bravo

AF:

0.0338

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.68

DANN

Benign

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over