chr14-64271676-G-A

Variant names:

• chr14-64271676-G-A
• rs1256040
• NM_001437.3:c.536-2765C>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.536-2765C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 152,118 control chromosomes in the GnomAD database, including 23,993 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 (23993 hom., cov: 33)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.171
• Publications: 11 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001437.3	c.536-2765C>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.536-2765C>T		intron_variant	Intron 3 of 8	1	NM_001437.3	ENSP00000343925.4

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84717 AN: 152000 Hom.: 23983 Cov.: 33

Gnomad AFR AF: 0.616

Gnomad AMI AF: 0.735

Gnomad AMR AF: 0.464

Gnomad ASJ AF: 0.578

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.451

Gnomad FIN AF: 0.560

Gnomad MID AF: 0.522

Gnomad NFE AF: 0.544

Gnomad OTH AF: 0.543

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

GnomAD4 genome AF: 0.557 AC: 84763 AN: 152118 Hom.: 23993 Cov.: 33 AF XY: 0.555 AC XY: 41256 AN XY: 74358

African (AFR) AF: 0.616 AC: 25552 AN: 41500

American (AMR) AF: 0.464 AC: 7089 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.578 AC: 2008 AN: 3472

East Asian (EAS) AF: 0.601 AC: 3105 AN: 5164

South Asian (SAS) AF: 0.451 AC: 2175 AN: 4826

European-Finnish (FIN) AF: 0.560 AC: 5920 AN: 10570

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.544 AC: 36961 AN: 67984

Other (OTH) AF: 0.539 AC: 1139 AN: 2114

Alfa AF: 0.557 Hom.: 3557

Bravo AF: 0.552

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	-0.91
CADD	Benign	3.1
DANN	Benign	0.31
PhyloP100		0.17
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: rs1256040; hg19: chr14-64738394;