rs932477

Variant names:

• chr6-151983461-A-G
• rs932477
• NM_000125.4:c.1097-28195A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000125.4(ESR1):​c.1097-28195A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.862 in 152,042 control chromosomes in the GnomAD database, including 56,824 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 0.86 (56806 hom., cov: 31)
  • Exomes 𝑓: 0.93 (18 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.174
• Publications: 14 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.897 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-28195A>G		intron_variant	Intron 4 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1097-28195A>G		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.862 AC: 130863 AN: 151882 Hom.: 56771 Cov.: 31

Gnomad AFR AF: 0.823

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.903

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.768

Gnomad FIN AF: 0.820

Gnomad MID AF: 0.940

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.877

GnomAD4 exome AF: 0.929 AC: 39 AN: 42 Hom.: 18 Cov.: 0 AF XY: 0.929 AC XY: 26 AN XY: 28

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.909 AC: 20 AN: 22

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 16 AN: 16

Other (OTH) AF: 0.500 AC: 1 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000298604), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.862 AC: 130956 AN: 152000 Hom.: 56806 Cov.: 31 AF XY: 0.857 AC XY: 63653 AN XY: 74276

African (AFR) AF: 0.824 AC: 34093 AN: 41398

American (AMR) AF: 0.903 AC: 13796 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 3202 AN: 3472

East Asian (EAS) AF: 0.610 AC: 3146 AN: 5154

South Asian (SAS) AF: 0.769 AC: 3700 AN: 4814

European-Finnish (FIN) AF: 0.820 AC: 8659 AN: 10566

Middle Eastern (MID) AF: 0.942 AC: 277 AN: 294

European-Non Finnish (NFE) AF: 0.903 AC: 61409 AN: 68000

Other (OTH) AF: 0.874 AC: 1845 AN: 2112

Alfa AF: 0.893 Hom.: 26412

Bravo AF: 0.865

Asia WGS AF: 0.697 AC: 2427 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.4
DANN	Benign	0.71
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs932477; hg19: chr6-152304596;