rs9478249

Variant names:

• chr6-151878296-T-G
• rs9478249
• NM_000125.4:c.644-2359T>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.644-2359T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 152,004 control chromosomes in the GnomAD database, including 13,596 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 0.42 (13596 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 3 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=-0.76).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.458 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.644-2359T>G		intron_variant	Intron 2 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.644-2359T>G		intron_variant	Intron 2 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.418 AC: 63520 AN: 151886 Hom.: 13592 Cov.: 32

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.482

Gnomad MID AF: 0.427

Gnomad NFE AF: 0.403

Gnomad OTH AF: 0.434

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

GnomAD4 genome AF: 0.418 AC: 63560 AN: 152004 Hom.: 13596 Cov.: 32 AF XY: 0.420 AC XY: 31173 AN XY: 74278

African (AFR) AF: 0.463 AC: 19211 AN: 41460

American (AMR) AF: 0.404 AC: 6158 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1655 AN: 3468

East Asian (EAS) AF: 0.255 AC: 1323 AN: 5180

South Asian (SAS) AF: 0.266 AC: 1284 AN: 4826

European-Finnish (FIN) AF: 0.482 AC: 5073 AN: 10528

Middle Eastern (MID) AF: 0.456 AC: 134 AN: 294

European-Non Finnish (NFE) AF: 0.403 AC: 27395 AN: 67978

Other (OTH) AF: 0.432 AC: 909 AN: 2104

Alfa AF: 0.408 Hom.: 10313

Bravo AF: 0.419

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		1.8
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: rs9478249; hg19: chr6-152199431;