rs9322335

Variant names:

• chr6-151878994-T-C
• rs9322335
• NM_000125.4:c.644-1661T>C

Variant summary

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

The NM_000125.4(ESR1):​c.644-1661T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.714 in 151,884 control chromosomes in the GnomAD database, including 39,034 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 0.71 (39034 hom., cov: 30)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0490
• Publications: 27 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.752 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.644-1661T>C		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.644-1661T>C		intron_variant	Intron 2 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108443 AN: 151766 Hom.: 39012 Cov.: 30

Gnomad AFR AF: 0.688

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.835

Gnomad EAS AF: 0.480

Gnomad SAS AF: 0.625

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.757

Gnomad OTH AF: 0.735

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

GnomAD4 genome AF: 0.714 AC: 108504 AN: 151884 Hom.: 39034 Cov.: 30 AF XY: 0.707 AC XY: 52516 AN XY: 74228

African (AFR) AF: 0.688 AC: 28497 AN: 41402

American (AMR) AF: 0.691 AC: 10555 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.835 AC: 2894 AN: 3464

East Asian (EAS) AF: 0.479 AC: 2453 AN: 5124

South Asian (SAS) AF: 0.625 AC: 3009 AN: 4812

European-Finnish (FIN) AF: 0.675 AC: 7113 AN: 10538

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.757 AC: 51459 AN: 67942

Other (OTH) AF: 0.730 AC: 1541 AN: 2110

Alfa AF: 0.748 Hom.: 130225

Bravo AF: 0.716

Asia WGS AF: 0.593 AC: 2063 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	2.9
DANN	Benign	0.71
PhyloP100		-0.049
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: rs9322335; hg19: chr6-152200129;