rs6927072

Variant names:

• chr6-151936552-T-G
• rs6927072
• NM_000125.4:c.761-7621T>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.761-7621T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.52 in 152,082 control chromosomes in the GnomAD database, including 22,913 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 0.52 (22913 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.533
• Publications: 17 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.761-7621T>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.761-7621T>G		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.521 AC: 79129 AN: 151964 Hom.: 22921 Cov.: 32

Gnomad AFR AF: 0.287

Gnomad AMI AF: 0.770

Gnomad AMR AF: 0.502

Gnomad ASJ AF: 0.714

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.382

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.712

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.563

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

GnomAD4 genome AF: 0.520 AC: 79141 AN: 152082 Hom.: 22913 Cov.: 32 AF XY: 0.515 AC XY: 38258 AN XY: 74344

African (AFR) AF: 0.287 AC: 11881 AN: 41456

American (AMR) AF: 0.502 AC: 7662 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.714 AC: 2479 AN: 3470

East Asian (EAS) AF: 0.215 AC: 1113 AN: 5174

South Asian (SAS) AF: 0.383 AC: 1850 AN: 4826

European-Finnish (FIN) AF: 0.642 AC: 6790 AN: 10576

Middle Eastern (MID) AF: 0.724 AC: 213 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45280 AN: 67992

Other (OTH) AF: 0.557 AC: 1174 AN: 2108

Alfa AF: 0.634 Hom.: 25784

Bravo AF: 0.496

Asia WGS AF: 0.309 AC: 1080 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.5
DANN	Benign	0.75
PhyloP100		0.53
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: rs6927072; hg19: chr6-152257687;