rs827422

Variant names:

• chr6-151835593-G-A
• rs827422
• NM_000125.4:c.453-7004G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-151835593-G-A
• chr6-151835593-G-C
• chr6-151835593-G-T

Variant summary

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

The ENST00000206249.8(ESR1):​c.453-7004G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.495 in 152,068 control chromosomes in the GnomAD database, including 19,214 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 0.50 (19214 hom., cov: 32)
• Consequence: ESR1 ENST00000206249.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.767
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.634 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000206249.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.453-7004G>A		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.453-7004G>A		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.453-7004G>A		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.453-7004G>A		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+27229G>A		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.-67-7004G>A		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.495 AC: 75245 AN: 151950 Hom.: 19202 Cov.: 32

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.644

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.565

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.535

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

GnomAD4 genome AF: 0.495 AC: 75297 AN: 152068 Hom.: 19214 Cov.: 32 AF XY: 0.502 AC XY: 37334 AN XY: 74308

African (AFR) AF: 0.391 AC: 16198 AN: 41480

American (AMR) AF: 0.645 AC: 9857 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.476 AC: 1652 AN: 3472

East Asian (EAS) AF: 0.617 AC: 3188 AN: 5166

South Asian (SAS) AF: 0.509 AC: 2449 AN: 4812

European-Finnish (FIN) AF: 0.565 AC: 5968 AN: 10558

Middle Eastern (MID) AF: 0.548 AC: 160 AN: 292

European-Non Finnish (NFE) AF: 0.503 AC: 34188 AN: 67982

Other (OTH) AF: 0.533 AC: 1125 AN: 2110

Alfa AF: 0.489 Hom.: 2283

Bravo AF: 0.503

Asia WGS AF: 0.558 AC: 1944 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.53
DANN	Benign	0.70
PhyloP100		-0.77
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: rs827422; hg19: chr6-152156728;