6-151887587-A-G

Variant names:

• chr6-151887587-A-G
• rs1913474
• NM_000125.4:c.760+6816A>G

Variant summary

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

The NM_000125.4(ESR1):​c.760+6816A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.778 in 151,898 control chromosomes in the GnomAD database, including 46,458 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 0.78 (46458 hom., cov: 29)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52
• Publications: 18 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.866 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.760+6816A>G		intron_variant	Intron 3 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.760+6816A>G		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.778 AC: 118036 AN: 151780 Hom.: 46424 Cov.: 29

Gnomad AFR AF: 0.873

Gnomad AMI AF: 0.860

Gnomad AMR AF: 0.730

Gnomad ASJ AF: 0.836

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.622

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.807

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.786

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

GnomAD4 genome AF: 0.778 AC: 118125 AN: 151898 Hom.: 46458 Cov.: 29 AF XY: 0.770 AC XY: 57135 AN XY: 74186

African (AFR) AF: 0.873 AC: 36194 AN: 41450

American (AMR) AF: 0.730 AC: 11128 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.836 AC: 2901 AN: 3470

East Asian (EAS) AF: 0.518 AC: 2659 AN: 5130

South Asian (SAS) AF: 0.623 AC: 2996 AN: 4808

European-Finnish (FIN) AF: 0.709 AC: 7452 AN: 10514

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.767 AC: 52122 AN: 67968

Other (OTH) AF: 0.783 AC: 1645 AN: 2102

Alfa AF: 0.788 Hom.: 6081

Bravo AF: 0.785

Asia WGS AF: 0.609 AC: 2120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.41
DANN	Benign	0.50
PhyloP100		-1.5
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: rs1913474; hg19: chr6-152208722;