14-64301584-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000554572.5(ESR2):c.-583-4G>A 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 0.335 in 151,926 control chromosomes in the GnomAD database, including 8,955 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (8953 hom., cov: 31)
  • Exomes 𝑓: 0.25 (2 hom.)
• Consequence: ESR2 ENST00000554572.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001395
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR2	NM_001291712.2	c.-583-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
ESR2	NM_001291723.1	c.-90-18509G>A		intron_variant
ESR2	XM_047431076.1	c.-90-18509G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR2	ENST00000554572.5	c.-583-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1
ESR2	ENST00000358599.9	c.-90-18509G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.335 AC: 50832 AN: 151768 Hom.: 8956 Cov.: 31

Gnomad AFR AF: 0.416

Gnomad AMI AF: 0.441

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.417

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.217

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.348

GnomAD4 exome AF: 0.250 AC: 10 AN: 40 Hom.: 2 Cov.: 0 AF XY: 0.233 AC XY: 7 AN XY: 30

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.250

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.335 AC: 50837 AN: 151886 Hom.: 8953 Cov.: 31 AF XY: 0.329 AC XY: 24410 AN XY: 74222

Gnomad4 AFR AF: 0.416

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.417

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.217

Gnomad4 NFE AF: 0.318

Gnomad4 OTH AF: 0.343

Alfa AF: 0.321 Hom.: 16093

Bravo AF: 0.338

Asia WGS AF: 0.292 AC: 1014 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.40
Dann	Benign	0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0060

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3020450; hg19: chr14-64768302;