6-151807507-A-G

Variant names:

• chr6-151807507-A-G
• rs867240
• ENST00000446550.1:c.-73A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_001122740.2(ESR1):​c.-73A>G variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 299,578 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (258 hom., cov: 31)
  • Exomes 𝑓: 0.0073 (37 hom.)
• Consequence: ESR1 NM_001122740.2 splice_region
• Scores: Splicing: ADA: 0.0003525
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.15
• Publications: 6 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=-0.44).
• BP6: Variant 6-151807507-A-G is Benign according to our data. Variant chr6-151807507-A-G is described in ClinVar as [Benign]. Clinvar id is 1268885.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.-406A>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.-406A>G		upstream_gene_variant		1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.0330 AC: 5022 AN: 152112 Hom.: 257 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.0273

GnomAD4 exome AF: 0.00732 AC: 1078 AN: 147348 Hom.: 37 Cov.: 0 AF XY: 0.00743 AC XY: 570 AN XY: 76692

African (AFR) AF: 0.115 AC: 589 AN: 5110

American (AMR) AF: 0.00940 AC: 85 AN: 9038

Ashkenazi Jewish (ASJ) AF: 0.000245 AC: 1 AN: 4074

East Asian (EAS) AF: 0.00 AC: 0 AN: 8808

South Asian (SAS) AF: 0.0116 AC: 248 AN: 21310

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6280

Middle Eastern (MID) AF: 0.0264 AC: 15 AN: 568

European-Non Finnish (NFE) AF: 0.000747 AC: 63 AN: 84316

Other (OTH) AF: 0.00982 AC: 77 AN: 7844

GnomAD4 genome AF: 0.0331 AC: 5033 AN: 152230 Hom.: 258 Cov.: 31 AF XY: 0.0319 AC XY: 2378 AN XY: 74434

African (AFR) AF: 0.110 AC: 4579 AN: 41524

American (AMR) AF: 0.0175 AC: 267 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5164

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00122 AC: 83 AN: 68014

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0229 Hom.: 92

Bravo AF: 0.0383

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	16
DANN	Benign	0.84
PhyloP100		1.1
PromoterAI		-0.028	Neutral
Mutation Taster		=283/17	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00035
dbscSNV1_RF	Benign	0.0040
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: rs867240; hg19: chr6-152128642;