rs944050

chr14-64233327-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001437.3(ESR2):c.1407-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,606,512 control chromosomes in the GnomAD database, including 6,384 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1003 hom., cov: 31)
  • Exomes 𝑓: 0.052 (5381 hom.)
• Consequence: ESR2 NM_001437.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004588
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.724

Genes affected

ESR2 (HGNC:3468): (estrogen receptor 2) This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

LOC124903328 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-64233327-T-C is Benign according to our data. Variant chr14-64233327-T-C is described in ClinVar as [Benign]. Clinvar id is 1267790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR2	NM_001437.3	c.1407-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000341099.6
LOC124903328	XR_007064205.1	n.90-1535T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR2	ENST00000341099.6	c.1407-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001437.3	P1

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12468 AN: 152034 Hom.: 1003 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00662

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.0411

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0774

GnomAD3 exomes AF: 0.0949 AC: 23740 AN: 250152 Hom.: 2906 AF XY: 0.0847 AC XY: 11447 AN XY: 135170

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.470

Gnomad SAS exome AF: 0.0304

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0519 AC: 75444 AN: 1454360 Hom.: 5381 Cov.: 32 AF XY: 0.0502 AC XY: 36241 AN XY: 721828

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.0128

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.0299

Gnomad4 FIN exome AF: 0.0831

Gnomad4 NFE exome AF: 0.0336

Gnomad4 OTH exome AF: 0.0668

GnomAD4 genome AF: 0.0821 AC: 12487 AN: 152152 Hom.: 1003 Cov.: 31 AF XY: 0.0853 AC XY: 6343 AN XY: 74394

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.456

Gnomad4 SAS AF: 0.0409

Gnomad4 FIN AF: 0.0936

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0794

Alfa AF: 0.0500 Hom.: 292

Bravo AF: 0.0888

Asia WGS AF: 0.208 AC: 721 AN: 3478

EpiCase AF: 0.0287

EpiControl AF: 0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 16553027) -

ESR2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	7.6
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.020		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: rs944050; hg19: chr14-64700045; COSMIC: COSV50829124; COSMIC: COSV50829124;