rs3778609

Variant names:

• chr6-151812052-C-T
• rs3778609
• NM_000125.4:c.452+3688C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000125.4(ESR1):​c.452+3688C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 151,976 control chromosomes in the GnomAD database, including 2,645 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 0.13 (2645 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0760
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.452+3688C>T		intron_variant	Intron 1 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.452+3688C>T		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20183 AN: 151858 Hom.: 2634 Cov.: 32

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.195

Gnomad ASJ AF: 0.0687

Gnomad EAS AF: 0.286

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0157

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.133 AC: 20225 AN: 151976 Hom.: 2645 Cov.: 32 AF XY: 0.136 AC XY: 10115 AN XY: 74304

African (AFR) AF: 0.318 AC: 13168 AN: 41432

American (AMR) AF: 0.195 AC: 2974 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0687 AC: 238 AN: 3462

East Asian (EAS) AF: 0.286 AC: 1476 AN: 5168

South Asian (SAS) AF: 0.179 AC: 862 AN: 4810

European-Finnish (FIN) AF: 0.0127 AC: 134 AN: 10586

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0157 AC: 1068 AN: 67938

Other (OTH) AF: 0.138 AC: 292 AN: 2110

Alfa AF: 0.0848 Hom.: 220

Bravo AF: 0.153

Asia WGS AF: 0.257 AC: 891 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Benign	0.91
PhyloP100		0.076
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3778609; hg19: chr6-152133187;