rs7450824

Variant names:

• chr6-152116968-T-C
• rs7450824
• ENST00000427531.6:c.851-8298T>C

Variant summary

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

The ENST00000427531.6(ESR1):​c.851-8298T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.196 in 152,126 control chromosomes in the GnomAD database, including 3,431 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 0.20 (3431 hom., cov: 32)
• Consequence: ESR1 ENST00000427531.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0600
• Publications: 12 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

ENSG00000284615 (HGNC:):

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 (EAS) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001328100.2	c.851-8298T>C		intron_variant	Intron 6 of 6		NP_001315029.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000427531.6	c.851-8298T>C		intron_variant	Intron 6 of 6	1		ENSP00000394721.2
ESR1	ENST00000641399.1	n.1071-1295T>C		intron_variant	Intron 6 of 6
ENSG00000284615	ENST00000641922.1	n.377-1295T>C		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29766 AN: 152008 Hom.: 3432 Cov.: 32

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.161

Gnomad EAS AF: 0.359

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.178

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

GnomAD4 genome AF: 0.196 AC: 29779 AN: 152126 Hom.: 3431 Cov.: 32 AF XY: 0.200 AC XY: 14846 AN XY: 74348

African (AFR) AF: 0.0836 AC: 3469 AN: 41514

American (AMR) AF: 0.184 AC: 2813 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 558 AN: 3472

East Asian (EAS) AF: 0.358 AC: 1853 AN: 5170

South Asian (SAS) AF: 0.277 AC: 1337 AN: 4820

European-Finnish (FIN) AF: 0.304 AC: 3208 AN: 10562

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15938 AN: 67990

Other (OTH) AF: 0.179 AC: 377 AN: 2112

Alfa AF: 0.214 Hom.: 6294

Bravo AF: 0.179

Asia WGS AF: 0.290 AC: 1014 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	2.1
DANN	Benign	0.45
PhyloP100		0.060
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs7450824; hg19: chr6-152438103;