14-64278681-T-C

Variant names:

• chr14-64278681-T-C
• rs1256033
• NM_001437.3:c.535+1300A>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.535+1300A>G 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 151,952 control chromosomes in the GnomAD database, including 24,712 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 (24712 hom., cov: 31)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.173
• Publications: 10 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437.3. 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_001437.3	MANE Select	c.535+1300A>G		intron	N/A	NP_001428.1
	ESR2	NM_001040275.1		c.535+1300A>G		intron	N/A	NP_001035365.1
	ESR2	NM_001291712.2		c.535+1300A>G		intron	N/A	NP_001278641.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000341099.6	TSL:1 MANE Select	c.535+1300A>G		intron	N/A	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.535+1300A>G		intron	N/A	ENSP00000335551.4
	ESR2	ENST00000554572.5	TSL:1	c.535+1300A>G		intron	N/A	ENSP00000450699.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85685 AN: 151834 Hom.: 24697 Cov.: 31

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.742

Gnomad AMR AF: 0.465

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.602

Gnomad SAS AF: 0.447

Gnomad FIN AF: 0.550

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.549

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

GnomAD4 genome AF: 0.564 AC: 85738 AN: 151952 Hom.: 24712 Cov.: 31 AF XY: 0.561 AC XY: 41614 AN XY: 74242

African (AFR) AF: 0.651 AC: 26945 AN: 41410

American (AMR) AF: 0.464 AC: 7089 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 1997 AN: 3466

East Asian (EAS) AF: 0.601 AC: 3106 AN: 5164

South Asian (SAS) AF: 0.446 AC: 2150 AN: 4816

European-Finnish (FIN) AF: 0.550 AC: 5794 AN: 10540

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.540 AC: 36687 AN: 67972

Other (OTH) AF: 0.545 AC: 1150 AN: 2110

Alfa AF: 0.536 Hom.: 3821

Bravo AF: 0.561

Asia WGS AF: 0.521 AC: 1813 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.6
DANN	Benign	0.75
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: rs1256033; hg19: chr14-64745399;