rs2273206

Variant names:

• chr6-152061176-G-T
• rs2273206
• NM_000125.4:c.1369+52G>T

Your query was ambiguous. Multiple possible variants found:

• chr6-152061176-G-T
• chr6-152061176-G-A
• chr6-152061176-G-C

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+52G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,580,140 control chromosomes in the GnomAD database, including 22,045 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (5300 hom., cov: 32)
  • Exomes 𝑓: 0.13 (16745 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.202
• Publications: 29 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-152061176-G-T is Benign according to our data. Variant chr6-152061176-G-T is described in ClinVar as Benign. ClinVar VariationId is 1274490.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1369+52G>T		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1375+52G>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1369+52G>T		intron	N/A	NP_001116212.1	P03372-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1369+52G>T		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.586+52G>T		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.850+52G>T		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33256 AN: 151818 Hom.: 5290 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.131

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.370

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.201

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.204

GnomAD2 exomes AF: 0.170 AC: 42445 AN: 249998 AF XY: 0.168

Gnomad AFR exome AF: 0.446

Gnomad AMR exome AF: 0.0611

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.378

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.134 AC: 191545 AN: 1428204 Hom.: 16745 Cov.: 25 AF XY: 0.136 AC XY: 97179 AN XY: 712696

African (AFR) AF: 0.449 AC: 14720 AN: 32768

American (AMR) AF: 0.0676 AC: 3018 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2718 AN: 25904

East Asian (EAS) AF: 0.341 AC: 13445 AN: 39456

South Asian (SAS) AF: 0.218 AC: 18674 AN: 85570

European-Finnish (FIN) AF: 0.199 AC: 10480 AN: 52790

Middle Eastern (MID) AF: 0.140 AC: 782 AN: 5572

European-Non Finnish (NFE) AF: 0.109 AC: 118194 AN: 1082226

Other (OTH) AF: 0.160 AC: 9514 AN: 59280

GnomAD4 genome AF: 0.219 AC: 33303 AN: 151936 Hom.: 5300 Cov.: 32 AF XY: 0.220 AC XY: 16350 AN XY: 74252

African (AFR) AF: 0.436 AC: 18048 AN: 41370

American (AMR) AF: 0.106 AC: 1623 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3470

East Asian (EAS) AF: 0.370 AC: 1913 AN: 5166

South Asian (SAS) AF: 0.230 AC: 1108 AN: 4812

European-Finnish (FIN) AF: 0.201 AC: 2119 AN: 10556

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.111 AC: 7522 AN: 67974

Other (OTH) AF: 0.206 AC: 435 AN: 2116

Alfa AF: 0.141 Hom.: 2984

Bravo AF: 0.220

Asia WGS AF: 0.295 AC: 1025 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.4
DANN	Benign	0.55
PhyloP100		-0.20
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: rs2273206; hg19: chr6-152382311; COSMIC: COSV52783060; COSMIC: COSV52783060;