rs3853251

Variant names:

• chr6-151839621-A-G
• rs3853251
• NM_000125.4:c.453-2976A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-151839621-A-G
• chr6-151839621-A-T

Variant summary

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

The NM_000125.4(ESR1):​c.453-2976A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 152,212 control chromosomes in the GnomAD database, including 5,494 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 0.25 (5494 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487
• Publications: 19 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.453-2976A>G		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.453-2976A>G		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38501 AN: 152094 Hom.: 5499 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.0333

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.385

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.266

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

GnomAD4 genome AF: 0.253 AC: 38507 AN: 152212 Hom.: 5494 Cov.: 32 AF XY: 0.245 AC XY: 18218 AN XY: 74410

African (AFR) AF: 0.146 AC: 6048 AN: 41564

American (AMR) AF: 0.256 AC: 3916 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1158 AN: 3470

East Asian (EAS) AF: 0.0334 AC: 173 AN: 5180

South Asian (SAS) AF: 0.235 AC: 1131 AN: 4820

European-Finnish (FIN) AF: 0.212 AC: 2252 AN: 10610

Middle Eastern (MID) AF: 0.380 AC: 111 AN: 292

European-Non Finnish (NFE) AF: 0.337 AC: 22873 AN: 67970

Other (OTH) AF: 0.262 AC: 553 AN: 2112

Alfa AF: 0.273 Hom.: 1796

Bravo AF: 0.250

Asia WGS AF: 0.125 AC: 436 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	1.8
DANN	Benign	0.54
PhyloP100		0.49
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: rs3853251; hg19: chr6-152160756; COSMIC: COSV52800683;