rs9322354

Positions:

• chr6-152060879-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.1236-112A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.156 in 857,232 control chromosomes in the GnomAD database, including 14,693 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: 0.14 (9393 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.129

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=-0.83).
• BP6: Variant 6-152060879-A-G is Benign according to our data. Variant chr6-152060879-A-G is described in ClinVar as [Benign]. Clinvar id is 1292722.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1236-112A>G		intron_variant		ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1236-112A>G		intron_variant		1	NM_000125.4	ENSP00000206249	P1

Frequencies

GnomAD3 genomes AF: 0.219 AC: 33277 AN: 151964 Hom.: 5290 Cov.: 32

Gnomad AFR AF: 0.436

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.107

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.142 AC: 100222 AN: 705150 Hom.: 9393 AF XY: 0.144 AC XY: 52886 AN XY: 366040

Gnomad4 AFR exome AF: 0.444

Gnomad4 AMR exome AF: 0.0772

Gnomad4 ASJ exome AF: 0.103

Gnomad4 EAS exome AF: 0.333

Gnomad4 SAS exome AF: 0.218

Gnomad4 FIN exome AF: 0.195

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.219 AC: 33324 AN: 152082 Hom.: 5300 Cov.: 32 AF XY: 0.220 AC XY: 16368 AN XY: 74344

Gnomad4 AFR AF: 0.436

Gnomad4 AMR AF: 0.106

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.230

Gnomad4 FIN AF: 0.200

Gnomad4 NFE AF: 0.111

Gnomad4 OTH AF: 0.205

Alfa AF: 0.198 Hom.: 682

Bravo AF: 0.220

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	-0.83
CADD	Benign	3.4
DANN	Benign	0.74

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: rs9322354; hg19: chr6-152382014;