chr14-64236875-G-T

Variant names:

• chr14-64236875-G-T
• rs1256061
• NM_001437.3:c.1226-1725C>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.1226-1725C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 151,468 control chromosomes in the GnomAD database, including 13,996 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 0.42 (13996 hom., cov: 29)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 29 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.484 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.1226-1725C>A		intron	N/A	NP_001428.1
	ESR2	NM_001040275.1		c.1226-1725C>A		intron	N/A	NP_001035365.1
	ESR2	NM_001291712.2		c.1226-1725C>A		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.1226-1725C>A		intron	N/A	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.1226-1725C>A		intron	N/A	ENSP00000335551.4
	ESR2	ENST00000554572.5	TSL:1	c.1226-1725C>A		intron	N/A	ENSP00000450699.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 63928 AN: 151352 Hom.: 13993 Cov.: 29

Gnomad AFR AF: 0.332

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.433

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.405

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

GnomAD4 genome AF: 0.422 AC: 63956 AN: 151468 Hom.: 13996 Cov.: 29 AF XY: 0.421 AC XY: 31163 AN XY: 73968

African (AFR) AF: 0.332 AC: 13711 AN: 41290

American (AMR) AF: 0.351 AC: 5344 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.482 AC: 1672 AN: 3470

East Asian (EAS) AF: 0.500 AC: 2565 AN: 5128

South Asian (SAS) AF: 0.339 AC: 1624 AN: 4796

European-Finnish (FIN) AF: 0.529 AC: 5504 AN: 10410

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.472 AC: 32021 AN: 67842

Other (OTH) AF: 0.404 AC: 849 AN: 2104

Alfa AF: 0.446 Hom.: 29182

Bravo AF: 0.406

Asia WGS AF: 0.417 AC: 1450 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.93
DANN	Benign	0.51
PhyloP100		-0.078
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: rs1256061; hg19: chr14-64703593;