6-152061782-T-C

Variant names:

• chr6-152061782-T-C
• rs6927127
• NM_000125.4:c.1369+658T>C

Variant summary

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

The NM_000125.4(ESR1):​c.1369+658T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,108 control chromosomes in the GnomAD database, including 5,283 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 0.22 (5283 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.672
• Publications: 10 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=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.43 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1369+658T>C		intron_variant	Intron 6 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1369+658T>C		intron_variant	Intron 6 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33238 AN: 151990 Hom.: 5273 Cov.: 32

Gnomad AFR AF: 0.435

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.204

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

GnomAD4 genome AF: 0.219 AC: 33285 AN: 152108 Hom.: 5283 Cov.: 32 AF XY: 0.220 AC XY: 16350 AN XY: 74366

African (AFR) AF: 0.436 AC: 18045 AN: 41420

American (AMR) AF: 0.106 AC: 1627 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 380 AN: 3466

East Asian (EAS) AF: 0.369 AC: 1903 AN: 5164

South Asian (SAS) AF: 0.228 AC: 1100 AN: 4818

European-Finnish (FIN) AF: 0.200 AC: 2118 AN: 10594

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7524 AN: 68026

Other (OTH) AF: 0.206 AC: 435 AN: 2114

Alfa AF: 0.165 Hom.: 460

Bravo AF: 0.220

Asia WGS AF: 0.295 AC: 1023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.4
DANN	Benign	0.73
PhyloP100		0.67
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: rs6927127; hg19: chr6-152382917;