rs3020383

Variant names:

• chr6-152095644-G-C
• rs3020383
• NM_000125.4:c.1553+1076G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152095644-G-C
• chr6-152095644-G-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.1553+1076G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0685 in 152,200 control chromosomes in the GnomAD database, including 433 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 0.069 (433 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.512
• Publications: 15 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. 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.1553+1076G>C		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1559+1076G>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1553+1076G>C		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.1553+1076G>C		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.770+1076G>C		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.851-29622G>C		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.0686 AC: 10429 AN: 152082 Hom.: 433 Cov.: 32

Gnomad AFR AF: 0.0310

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.0684

Gnomad ASJ AF: 0.0891

Gnomad EAS AF: 0.0997

Gnomad SAS AF: 0.0895

Gnomad FIN AF: 0.0574

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0866

Gnomad OTH AF: 0.0834

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

GnomAD4 genome AF: 0.0685 AC: 10429 AN: 152200 Hom.: 433 Cov.: 32 AF XY: 0.0675 AC XY: 5019 AN XY: 74404

African (AFR) AF: 0.0309 AC: 1284 AN: 41550

American (AMR) AF: 0.0683 AC: 1045 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0891 AC: 309 AN: 3468

East Asian (EAS) AF: 0.0997 AC: 515 AN: 5164

South Asian (SAS) AF: 0.0897 AC: 432 AN: 4814

European-Finnish (FIN) AF: 0.0574 AC: 608 AN: 10592

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.0866 AC: 5892 AN: 68006

Other (OTH) AF: 0.0830 AC: 175 AN: 2108

Alfa AF: 0.0394 Hom.: 31

Bravo AF: 0.0685

Asia WGS AF: 0.0840 AC: 292 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.3
DANN	Benign	0.55
PhyloP100		0.51
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: rs3020383; hg19: chr6-152416779; COSMIC: COSV52801312; COSMIC: COSV52801312;