rs2273207

Variant names:

• chr6-152061190-A-G
• rs2273207
• NM_000125.4:c.1369+66A>G

Variant summary

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

The NM_000125.4(ESR1):​c.1369+66A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 1,487,136 control chromosomes in the GnomAD database, including 9,545 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1210 hom., cov: 32)
  • Exomes 𝑓: 0.099 (8335 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.83
• Publications: 14 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=-0.81).
• BP6: Variant 6-152061190-A-G is Benign according to our data. Variant chr6-152061190-A-G is described in ClinVar as Benign. ClinVar VariationId is 1248080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1369+66A>G		intron_variant	Intron 6 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1369+66A>G		intron_variant	Intron 6 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17063 AN: 152032 Hom.: 1211 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0934

Gnomad AMR AF: 0.0649

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.334

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0821

Gnomad OTH AF: 0.112

GnomAD4 exome AF: 0.0990 AC: 132165 AN: 1334986 Hom.: 8335 AF XY: 0.101 AC XY: 67880 AN XY: 671280

African (AFR) AF: 0.128 AC: 3947 AN: 30930

American (AMR) AF: 0.0406 AC: 1804 AN: 44452

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2535 AN: 25286

East Asian (EAS) AF: 0.318 AC: 12432 AN: 39052

South Asian (SAS) AF: 0.159 AC: 13301 AN: 83428

European-Finnish (FIN) AF: 0.175 AC: 9080 AN: 51738

Middle Eastern (MID) AF: 0.0986 AC: 509 AN: 5162

European-Non Finnish (NFE) AF: 0.0822 AC: 82127 AN: 998666

Other (OTH) AF: 0.114 AC: 6430 AN: 56272

GnomAD4 genome AF: 0.112 AC: 17074 AN: 152150 Hom.: 1210 Cov.: 32 AF XY: 0.117 AC XY: 8698 AN XY: 74398

African (AFR) AF: 0.129 AC: 5366 AN: 41486

American (AMR) AF: 0.0647 AC: 989 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3470

East Asian (EAS) AF: 0.334 AC: 1729 AN: 5172

South Asian (SAS) AF: 0.170 AC: 817 AN: 4820

European-Finnish (FIN) AF: 0.177 AC: 1880 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0822 AC: 5586 AN: 67996

Other (OTH) AF: 0.113 AC: 238 AN: 2114

Alfa AF: 0.0923 Hom.: 2911

Bravo AF: 0.103

Asia WGS AF: 0.236 AC: 820 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 30, 2018

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	-0.81
CADD	Benign	8.6
DANN	Benign	0.56
PhyloP100		1.8
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: rs2273207; hg19: chr6-152382325; COSMIC: COSV52781962; COSMIC: COSV52781962;