rs2207396

Variant names:

• chr6-152061247-G-A
• rs2207396
• NM_000125.4:c.1369+123G>A

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+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 934,618 control chromosomes in the GnomAD database, including 25,426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.23 (4025 hom., cov: 33)
  • Exomes 𝑓: 0.22 (21401 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.180
• Publications: 34 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=-0.85).
• BP6: Variant 6-152061247-G-A is Benign according to our data. Variant chr6-152061247-G-A is described in ClinVar as Benign. ClinVar VariationId is 1268561.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.333 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1369+123G>A		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+123G>A		intron_variant	Intron 6 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34375 AN: 151920 Hom.: 4017 Cov.: 33

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.237

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.225

Gnomad OTH AF: 0.199

GnomAD4 exome AF: 0.223 AC: 174871 AN: 782580 Hom.: 21401 AF XY: 0.231 AC XY: 94549 AN XY: 410086

African (AFR) AF: 0.251 AC: 5036 AN: 20058

American (AMR) AF: 0.105 AC: 4106 AN: 39136

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 3648 AN: 21488

East Asian (EAS) AF: 0.194 AC: 6710 AN: 34666

South Asian (SAS) AF: 0.350 AC: 23931 AN: 68442

European-Finnish (FIN) AF: 0.236 AC: 9426 AN: 39882

Middle Eastern (MID) AF: 0.233 AC: 682 AN: 2930

European-Non Finnish (NFE) AF: 0.218 AC: 112881 AN: 518318

Other (OTH) AF: 0.224 AC: 8451 AN: 37660

GnomAD4 genome AF: 0.226 AC: 34421 AN: 152038 Hom.: 4025 Cov.: 33 AF XY: 0.227 AC XY: 16896 AN XY: 74306

African (AFR) AF: 0.250 AC: 10356 AN: 41462

American (AMR) AF: 0.145 AC: 2217 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3468

East Asian (EAS) AF: 0.206 AC: 1066 AN: 5174

South Asian (SAS) AF: 0.347 AC: 1671 AN: 4820

European-Finnish (FIN) AF: 0.237 AC: 2501 AN: 10548

Middle Eastern (MID) AF: 0.214 AC: 63 AN: 294

European-Non Finnish (NFE) AF: 0.225 AC: 15328 AN: 67982

Other (OTH) AF: 0.198 AC: 419 AN: 2116

Alfa AF: 0.223 Hom.: 17301

Bravo AF: 0.217

Asia WGS AF: 0.281 AC: 978 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.91
DANN	Benign	0.73
PhyloP100		0.18
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: rs2207396; hg19: chr6-152382382; COSMIC: COSV52801204; COSMIC: COSV52801204;