6-151957606-C-T

Variant names:

• chr6-151957606-C-T
• rs3020317
• NM_000125.4:c.1096+13098C>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.1096+13098C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.762 in 151,958 control chromosomes in the GnomAD database, including 44,471 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 0.76 (44471 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0210
• Publications: 19 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=-0.96).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.804 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.1096+13098C>T		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1102+13098C>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1096+13098C>T		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.1096+13098C>T		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-103385C>T		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.577+13098C>T		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.762 AC: 115774 AN: 151840 Hom.: 44467 Cov.: 31

Gnomad AFR AF: 0.712

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.791

Gnomad ASJ AF: 0.809

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.592

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.789

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

GnomAD4 genome AF: 0.762 AC: 115813 AN: 151958 Hom.: 44471 Cov.: 31 AF XY: 0.757 AC XY: 56197 AN XY: 74242

African (AFR) AF: 0.711 AC: 29463 AN: 41422

American (AMR) AF: 0.790 AC: 12078 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.809 AC: 2804 AN: 3466

East Asian (EAS) AF: 0.573 AC: 2945 AN: 5142

South Asian (SAS) AF: 0.593 AC: 2852 AN: 4810

European-Finnish (FIN) AF: 0.752 AC: 7928 AN: 10542

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55054 AN: 67986

Other (OTH) AF: 0.782 AC: 1646 AN: 2106

Alfa AF: 0.790 Hom.: 29484

Bravo AF: 0.763

Asia WGS AF: 0.573 AC: 1995 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	3.0
DANN	Benign	0.71
PhyloP100		-0.021
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: rs3020317; hg19: chr6-152278741;