6-151984370-C-T

Variant names:

• chr6-151984370-C-T
• rs3020328
• NM_000125.4:c.1097-27286C>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.1097-27286C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 151,852 control chromosomes in the GnomAD database, including 29,068 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 0.57 (29068 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.729 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.1097-27286C>T		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1103-27286C>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1097-27286C>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.1097-27286C>T		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-76621C>T		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.578-27286C>T		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.572 AC: 86748 AN: 151734 Hom.: 29072 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.727

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.327

Gnomad SAS AF: 0.489

Gnomad FIN AF: 0.723

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.734

Gnomad OTH AF: 0.622

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

GnomAD4 genome AF: 0.571 AC: 86760 AN: 151852 Hom.: 29068 Cov.: 32 AF XY: 0.572 AC XY: 42449 AN XY: 74222

African (AFR) AF: 0.221 AC: 9114 AN: 41302

American (AMR) AF: 0.727 AC: 11097 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2755 AN: 3468

East Asian (EAS) AF: 0.328 AC: 1688 AN: 5146

South Asian (SAS) AF: 0.491 AC: 2363 AN: 4812

European-Finnish (FIN) AF: 0.723 AC: 7635 AN: 10558

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.734 AC: 49930 AN: 67984

Other (OTH) AF: 0.616 AC: 1298 AN: 2108

Alfa AF: 0.667 Hom.: 7528

Bravo AF: 0.556

Asia WGS AF: 0.399 AC: 1391 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.5
DANN	Benign	0.76
PhyloP100		-0.27
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: rs3020328; hg19: chr6-152305505;