rs3020370

Variant names:

• chr6-152055047-G-C
• rs3020370
• NM_000125.4:c.1236-5944G>C

Your query was ambiguous. Multiple possible variants found:

• chr6-152055047-G-C
• chr6-152055047-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.1236-5944G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 152,006 control chromosomes in the GnomAD database, including 3,280 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 (3280 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.803
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1236-5944G>C		intron_variant	Intron 5 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1236-5944G>C		intron_variant	Intron 5 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.202 AC: 30738 AN: 151888 Hom.: 3274 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.170

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.182

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

GnomAD4 genome AF: 0.202 AC: 30770 AN: 152006 Hom.: 3280 Cov.: 32 AF XY: 0.204 AC XY: 15162 AN XY: 74274

African (AFR) AF: 0.166 AC: 6864 AN: 41468

American (AMR) AF: 0.136 AC: 2072 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 590 AN: 3468

East Asian (EAS) AF: 0.216 AC: 1113 AN: 5148

South Asian (SAS) AF: 0.346 AC: 1671 AN: 4826

European-Finnish (FIN) AF: 0.235 AC: 2475 AN: 10526

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.226 AC: 15329 AN: 67976

Other (OTH) AF: 0.182 AC: 384 AN: 2112

Alfa AF: 0.132 Hom.: 255

Bravo AF: 0.189

Asia WGS AF: 0.278 AC: 968 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.1
DANN	Benign	0.65
PhyloP100		0.80
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: rs3020370; hg19: chr6-152376182; COSMIC: COSV52801195;