NM_000125.4:c.761-30715T>C

Variant names:

• chr6-151913458-T-C
• rs6557171
• NM_000125.4:c.761-30715T>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.761-30715T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 152,118 control chromosomes in the GnomAD database, including 29,097 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 0.61 (29097 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.05
• Publications: 26 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=-0.63).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.677 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.761-30715T>C		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.767-30715T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.761-30715T>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.761-30715T>C		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+105094T>C		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.242-30715T>C		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.612 AC: 93016 AN: 152000 Hom.: 29080 Cov.: 33

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.535

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.471

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.753

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.634

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

GnomAD4 genome AF: 0.612 AC: 93088 AN: 152118 Hom.: 29097 Cov.: 33 AF XY: 0.605 AC XY: 45035 AN XY: 74392

African (AFR) AF: 0.538 AC: 22337 AN: 41492

American (AMR) AF: 0.535 AC: 8170 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.764 AC: 2651 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2078 AN: 5174

South Asian (SAS) AF: 0.473 AC: 2283 AN: 4822

European-Finnish (FIN) AF: 0.654 AC: 6913 AN: 10572

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46385 AN: 67994

Other (OTH) AF: 0.633 AC: 1338 AN: 2114

Alfa AF: 0.665 Hom.: 55328

Bravo AF: 0.598

Asia WGS AF: 0.463 AC: 1613 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	16
DANN	Benign	0.72
PhyloP100		1.1
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: rs6557171; hg19: chr6-152234593;