rs2273207

Positions:

• chr6-152061190-A-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
ESR1	NM_000125.4	c.1369+66A>G		intron_variant		ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.1369+66A>G		intron_variant		1	NM_000125.4	P1

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

Gnomad4 AFR exome AF: 0.128

Gnomad4 AMR exome AF: 0.0406

Gnomad4 ASJ exome AF: 0.100

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.159

Gnomad4 FIN exome AF: 0.175

Gnomad4 NFE exome AF: 0.0822

Gnomad4 OTH exome AF: 0.114

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

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.0647

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.334

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.177

Gnomad4 NFE AF: 0.0822

Gnomad4 OTH AF: 0.113

Alfa AF: 0.0879 Hom.: 1149

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.6
DANN	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs2273207; hg19: chr6-152382325; COSMIC: COSV52781962; COSMIC: COSV52781962;