14-64287643-G-T

Variant names:

• chr14-64287643-G-T
• rs6573553
• NM_001437.3:c.-90-4568C>A

Variant summary

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

The NM_001437.3(ESR2):​c.-90-4568C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.501 in 151,938 control chromosomes in the GnomAD database, including 19,753 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 0.50 (19753 hom., cov: 31)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179
• Publications: 14 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 = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001437.3	c.-90-4568C>A		intron_variant	Intron 1 of 8	ENST00000341099.6	NP_001428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000341099.6	c.-90-4568C>A		intron_variant	Intron 1 of 8	1	NM_001437.3	ENSP00000343925.4

Frequencies

GnomAD3 genomes AF: 0.501 AC: 76132 AN: 151820 Hom.: 19743 Cov.: 31

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.736

Gnomad AMR AF: 0.423

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.225

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.496

Gnomad OTH AF: 0.498

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

GnomAD4 genome AF: 0.501 AC: 76178 AN: 151938 Hom.: 19753 Cov.: 31 AF XY: 0.493 AC XY: 36629 AN XY: 74232

African (AFR) AF: 0.593 AC: 24560 AN: 41436

American (AMR) AF: 0.423 AC: 6455 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1951 AN: 3468

East Asian (EAS) AF: 0.226 AC: 1169 AN: 5168

South Asian (SAS) AF: 0.392 AC: 1880 AN: 4802

European-Finnish (FIN) AF: 0.438 AC: 4619 AN: 10538

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.496 AC: 33693 AN: 67936

Other (OTH) AF: 0.491 AC: 1037 AN: 2112

Alfa AF: 0.471 Hom.: 8125

Bravo AF: 0.504

Asia WGS AF: 0.348 AC: 1212 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	1.2
DANN	Benign	0.49
PhyloP100		0.18
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: rs6573553; hg19: chr14-64754361;