rs2228480

Variant names:

• chr6-152098960-G-A
• rs2228480
• NM_000125.4:c.1782G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-152098960-G-A
• chr6-152098960-G-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001291230.2(ESR1):​c.1788G>A​(p.Thr596Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 1,612,120 control chromosomes in the GnomAD database, including 29,351 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2469 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26882 hom.)
• Consequence: ESR1 NM_001291230.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -0.344
• Publications: 182 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-152098960-G-A is Benign according to our data. Variant chr6-152098960-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1263746.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.344 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291230.2. 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.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.1788G>A	p.Thr596Thr	synonymous	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.1782G>A	p.Thr594Thr	synonymous	Exon 9 of 9	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1782G>A	p.Thr594Thr	synonymous	Exon 8 of 8	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.999G>A	p.Thr333Thr	synonymous	Exon 4 of 4	ENSP00000384064.1
	ESR1	ENST00000456483.3	TSL:1	c.*657G>A		3_prime_UTR	Exon 5 of 5	ENSP00000415934.3

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27192 AN: 152006 Hom.: 2462 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.205

Gnomad SAS AF: 0.190

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.0892

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.155

GnomAD2 exomes AF: 0.194 AC: 48493 AN: 250380 AF XY: 0.190

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.271

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.219

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.170

GnomAD4 exome AF: 0.190 AC: 276902 AN: 1459992 Hom.: 26882 Cov.: 31 AF XY: 0.189 AC XY: 136931 AN XY: 726374

African (AFR) AF: 0.150 AC: 5015 AN: 33448

American (AMR) AF: 0.265 AC: 11831 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3666 AN: 26128

East Asian (EAS) AF: 0.192 AC: 7631 AN: 39684

South Asian (SAS) AF: 0.191 AC: 16429 AN: 86220

European-Finnish (FIN) AF: 0.186 AC: 9911 AN: 53360

Middle Eastern (MID) AF: 0.111 AC: 641 AN: 5764

European-Non Finnish (NFE) AF: 0.190 AC: 210969 AN: 1110376

Other (OTH) AF: 0.179 AC: 10809 AN: 60334

GnomAD4 genome AF: 0.179 AC: 27235 AN: 152128 Hom.: 2469 Cov.: 32 AF XY: 0.181 AC XY: 13439 AN XY: 74386

African (AFR) AF: 0.154 AC: 6380 AN: 41524

American (AMR) AF: 0.231 AC: 3523 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3468

East Asian (EAS) AF: 0.206 AC: 1061 AN: 5158

South Asian (SAS) AF: 0.190 AC: 915 AN: 4822

European-Finnish (FIN) AF: 0.183 AC: 1935 AN: 10590

Middle Eastern (MID) AF: 0.0856 AC: 25 AN: 292

European-Non Finnish (NFE) AF: 0.184 AC: 12499 AN: 67982

Other (OTH) AF: 0.162 AC: 342 AN: 2106

Alfa AF: 0.180 Hom.: 10220

Bravo AF: 0.182

Asia WGS AF: 0.212 AC: 737 AN: 3478

EpiCase AF: 0.174

EpiControl AF: 0.169

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	ESR1-related disorder (1)
-	-	1	Familial cancer of breast;C1832662:Myocardial infarction, susceptibility to;C3809250:Estrogen resistance syndrome;C3887485:Migraine with or without aura, susceptibility to, 1 (1)
-	-	1	not provided (1)
-	-	-	Migraine with or without aura, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.093
DANN	Benign	0.50
PhyloP100		-0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2228480; hg19: chr6-152420095; COSMIC: COSV52780915; COSMIC: COSV52780915;