14-64301584-C-T

Variant names:

• chr14-64301584-C-T
• rs3020450
• ENST00000554572.5:c.-583-4G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000554572.5(ESR2):​c.-583-4G>A variant causes a splice region, 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, intron
• Scores: Splicing: ADA: 0.00001395
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 48 publications found

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]

ESR2 Gene-Disease associations (from GenCC):

• male infertility with azoospermia or oligozoospermia due to single gene mutation

  Inheritance: AR Classification: MODERATE Submitted by: King Faisal Specialist Hospital and Research Center
• familial medullary thyroid carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• ovarian dysgenesis 8

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000554572.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	NM_001291712.2		c.-583-4G>A		splice_region intron	N/A	NP_001278641.1
	ESR2	NM_001291723.1		c.-90-18509G>A		intron	N/A	NP_001278652.1
	ESR2	NR_073496.2		n.717-18509G>A		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000554572.5	TSL:1	c.-583-4G>A		splice_region intron	N/A	ENSP00000450699.1
	ESR2	ENST00000358599.9	TSL:2	c.-90-18509G>A		intron	N/A	ENSP00000351412.5

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

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.233 AC: 7 AN: 30

Other (OTH) AF: 0.00 AC: 0 AN: 2

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

African (AFR) AF: 0.416 AC: 17208 AN: 41390

American (AMR) AF: 0.286 AC: 4360 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.417 AC: 1446 AN: 3466

East Asian (EAS) AF: 0.202 AC: 1046 AN: 5168

South Asian (SAS) AF: 0.343 AC: 1650 AN: 4814

European-Finnish (FIN) AF: 0.217 AC: 2287 AN: 10528

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21594 AN: 67952

Other (OTH) AF: 0.343 AC: 721 AN: 2102

Alfa AF: 0.325 Hom.: 34149

Bravo AF: 0.338

Asia WGS AF: 0.292 AC: 1014 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.32
PhyloP100		-1.9
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3020450; hg19: chr14-64768302;