rs1256031

Variant names:

• chr14-64279461-G-A
• rs1256031
• NM_001437.3:c.535+520C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-64279461-G-A
• chr14-64279461-G-C
• chr14-64279461-G-T

Variant summary

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

The NM_001437.3(ESR2):​c.535+520C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,822 control chromosomes in the GnomAD database, including 24,697 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 0.56 (24697 hom., cov: 31)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 47 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001437.3	c.535+520C>T		intron_variant	Intron 3 of 8	ENST00000341099.6	NP_001428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000341099.6	c.535+520C>T		intron_variant	Intron 3 of 8	1	NM_001437.3	ENSP00000343925.4

Frequencies

GnomAD3 genomes AF: 0.565 AC: 85639 AN: 151702 Hom.: 24681 Cov.: 31

Gnomad AFR AF: 0.650

Gnomad AMI AF: 0.744

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.448

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.550

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

GnomAD4 genome AF: 0.564 AC: 85694 AN: 151822 Hom.: 24697 Cov.: 31 AF XY: 0.561 AC XY: 41604 AN XY: 74168

African (AFR) AF: 0.650 AC: 26917 AN: 41388

American (AMR) AF: 0.465 AC: 7090 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 1997 AN: 3468

East Asian (EAS) AF: 0.601 AC: 3110 AN: 5172

South Asian (SAS) AF: 0.447 AC: 2153 AN: 4816

European-Finnish (FIN) AF: 0.552 AC: 5800 AN: 10500

Middle Eastern (MID) AF: 0.497 AC: 146 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36653 AN: 67906

Other (OTH) AF: 0.545 AC: 1151 AN: 2110

Alfa AF: 0.546 Hom.: 60136

Bravo AF: 0.561

Asia WGS AF: 0.522 AC: 1816 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.99
DANN	Benign	0.57
PhyloP100		-1.0
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: rs1256031; hg19: chr14-64746179; COSMIC: COSV99963490;