6-151841182-C-T

Variant names:

• chr6-151841182-C-T
• rs9322331
• NM_000125.4:c.453-1415C>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.453-1415C>T 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 152,078 control chromosomes in the GnomAD database, including 5,489 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 (5489 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.498
• Publications: 28 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 = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.453-1415C>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.453-1415C>T		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.253 AC: 38466 AN: 151958 Hom.: 5494 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.255

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.0332

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.336

Gnomad OTH AF: 0.265

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

GnomAD4 genome AF: 0.253 AC: 38475 AN: 152078 Hom.: 5489 Cov.: 33 AF XY: 0.245 AC XY: 18218 AN XY: 74370

African (AFR) AF: 0.146 AC: 6056 AN: 41488

American (AMR) AF: 0.255 AC: 3894 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1160 AN: 3470

East Asian (EAS) AF: 0.0333 AC: 172 AN: 5170

South Asian (SAS) AF: 0.234 AC: 1129 AN: 4824

European-Finnish (FIN) AF: 0.212 AC: 2248 AN: 10584

Middle Eastern (MID) AF: 0.384 AC: 113 AN: 294

European-Non Finnish (NFE) AF: 0.336 AC: 22861 AN: 67964

Other (OTH) AF: 0.261 AC: 550 AN: 2108

Alfa AF: 0.308 Hom.: 20416

Bravo AF: 0.250

Asia WGS AF: 0.126 AC: 439 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	1.1
DANN	Benign	0.55
PhyloP100		-0.50
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: rs9322331; hg19: chr6-152162317;