rs4365213

Variant names:

• chr14-64253546-T-C
• rs4365213
• NM_001437.3:c.1091+3680A>G

Variant summary

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

The NM_001437.3(ESR2):​c.1091+3680A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.411 in 148,068 control chromosomes in the GnomAD database, including 12,637 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.41 (12637 hom., cov: 27)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.713
• Publications: 21 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=-0.8).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001437.3	c.1091+3680A>G		intron_variant	Intron 6 of 8	ENST00000341099.6	NP_001428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000341099.6	c.1091+3680A>G		intron_variant	Intron 6 of 8	1	NM_001437.3	ENSP00000343925.4

Frequencies

GnomAD3 genomes AF: 0.411 AC: 60847 AN: 147940 Hom.: 12639 Cov.: 27

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.591

Gnomad AMR AF: 0.384

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.308

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.429

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.412

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.411 AC: 60871 AN: 148068 Hom.: 12637 Cov.: 27 AF XY: 0.408 AC XY: 29326 AN XY: 71952

African (AFR) AF: 0.377 AC: 15144 AN: 40160

American (AMR) AF: 0.384 AC: 5693 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1618 AN: 3432

East Asian (EAS) AF: 0.229 AC: 1142 AN: 4992

South Asian (SAS) AF: 0.307 AC: 1397 AN: 4552

European-Finnish (FIN) AF: 0.465 AC: 4501 AN: 9688

Middle Eastern (MID) AF: 0.403 AC: 117 AN: 290

European-Non Finnish (NFE) AF: 0.445 AC: 29878 AN: 67144

Other (OTH) AF: 0.407 AC: 844 AN: 2072

Alfa AF: 0.429 Hom.: 53995

Bravo AF: 0.404

Asia WGS AF: 0.284 AC: 991 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.2
DANN	Benign	0.83
PhyloP100		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4365213; hg19: chr14-64720264;