chr6-151805689-T-G

Variant names:

• chr6-151805689-T-G
• rs2071454
• ENST00000404742.5:c.-70-2154T>G

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-2154T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 152,026 control chromosomes in the GnomAD database, including 4,698 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 (4696 hom., cov: 32)
  • Exomes 𝑓: 0.12 (2 hom.)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.507
• Publications: 13 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=-0.56).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.396 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000404742.5. 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_001122742.2		c.-70-2154T>G		intron	N/A	NP_001116214.1
	ESR1	NM_001385568.1		c.-70-2154T>G		intron	N/A	NP_001372497.1
	ESR1	NM_001385570.1		c.-70-2154T>G		intron	N/A	NP_001372499.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000404742.5	TSL:1	c.-70-2154T>G		intron	N/A	ENSP00000385373.1
	ESR1	ENST00000473497.5	TSL:1	n.205-2154T>G		intron	N/A
	ESR1	ENST00000338799.9	TSL:5	c.-202T>G		5_prime_UTR	Exon 1 of 9	ENSP00000342630.5

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32588 AN: 151676 Hom.: 4681 Cov.: 32

Gnomad AFR AF: 0.401

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.288

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.116 AC: 27 AN: 232 Hom.: 2 Cov.: 0 AF XY: 0.127 AC XY: 19 AN XY: 150

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.136 AC: 15 AN: 110

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0577 AC: 6 AN: 104

Other (OTH) AF: 0.286 AC: 4 AN: 14

GnomAD4 genome AF: 0.215 AC: 32644 AN: 151794 Hom.: 4696 Cov.: 32 AF XY: 0.218 AC XY: 16170 AN XY: 74202

African (AFR) AF: 0.401 AC: 16645 AN: 41460

American (AMR) AF: 0.232 AC: 3547 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 467 AN: 3434

East Asian (EAS) AF: 0.288 AC: 1486 AN: 5160

South Asian (SAS) AF: 0.217 AC: 1044 AN: 4820

European-Finnish (FIN) AF: 0.148 AC: 1556 AN: 10548

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7327 AN: 67796

Other (OTH) AF: 0.204 AC: 430 AN: 2108

Alfa AF: 0.132 Hom.: 1532

Bravo AF: 0.227

Asia WGS AF: 0.281 AC: 975 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.92
PhyloP100		0.51
Mutation Taster		=300/0	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: rs2071454; hg19: chr6-152126824;