6-151807496-C-G

Variant names:

• chr6-151807496-C-G
• rs867239
• ENST00000446550.1:c.-84C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001122740.2(ESR1):​c.-84C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 294,968 control chromosomes in the GnomAD database, including 1,178 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (831 hom., cov: 31)
  • Exomes 𝑓: 0.031 (347 hom.)
• Consequence: ESR1 NM_001122740.2 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.132
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-151807496-C-G is Benign according to our data. Variant chr6-151807496-C-G is described in ClinVar as [Benign]. Clinvar id is 1290579.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.-417C>G		upstream_gene_variant		ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.-417C>G		upstream_gene_variant		1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.0694 AC: 10548 AN: 152096 Hom.: 830 Cov.: 31

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.145

Gnomad SAS AF: 0.0261

Gnomad FIN AF: 0.00613

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.0702

GnomAD4 exome AF: 0.0306 AC: 4367 AN: 142750 Hom.: 347 Cov.: 0 AF XY: 0.0302 AC XY: 2247 AN XY: 74424

African (AFR) AF: 0.175 AC: 843 AN: 4814

American (AMR) AF: 0.171 AC: 1478 AN: 8646

Ashkenazi Jewish (ASJ) AF: 0.00315 AC: 12 AN: 3810

East Asian (EAS) AF: 0.144 AC: 1167 AN: 8078

South Asian (SAS) AF: 0.0203 AC: 434 AN: 21358

European-Finnish (FIN) AF: 0.00451 AC: 28 AN: 6202

Middle Eastern (MID) AF: 0.0289 AC: 16 AN: 554

European-Non Finnish (NFE) AF: 0.00203 AC: 166 AN: 81796

Other (OTH) AF: 0.0298 AC: 223 AN: 7492

GnomAD4 genome AF: 0.0694 AC: 10567 AN: 152218 Hom.: 831 Cov.: 31 AF XY: 0.0706 AC XY: 5252 AN XY: 74424

African (AFR) AF: 0.168 AC: 6992 AN: 41500

American (AMR) AF: 0.148 AC: 2262 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.146 AC: 750 AN: 5152

South Asian (SAS) AF: 0.0255 AC: 123 AN: 4830

European-Finnish (FIN) AF: 0.00613 AC: 65 AN: 10610

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00303 AC: 206 AN: 68026

Other (OTH) AF: 0.0728 AC: 154 AN: 2116

Alfa AF: 0.00921 Hom.: 9

Bravo AF: 0.0872

Asia WGS AF: 0.114 AC: 396 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		-0.13
PromoterAI		-0.064	Neutral
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: rs867239; hg19: chr6-152128631;