14-64233327-T-C

Variant names:

• chr14-64233327-T-C
• rs944050
• ENST00000557772.5:c.*1630A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000557772.5(ESR2):​c.*1630A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,606,512 control chromosomes in the GnomAD database, including 6,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (1003 hom., cov: 31)
  • Exomes 𝑓: 0.052 (5381 hom.)
• Consequence: ESR2 ENST00000557772.5 3_prime_UTR
• Scores: Splicing: ADA: 0.00004588
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.724
• 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)

LOC124903328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 14-64233327-T-C is Benign according to our data. Variant chr14-64233327-T-C is described in ClinVar as Benign. ClinVar VariationId is 1267790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000557772.5. 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.1407-4A>G		splice_region intron	N/A	NP_001428.1
	ESR2	NM_001040275.1		c.1406+1643A>G		intron	N/A	NP_001035365.1
	ESR2	NM_001291712.2		c.1406+1643A>G		intron	N/A	NP_001278641.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000557772.5	TSL:1	c.*1630A>G		3_prime_UTR	Exon 7 of 7	ENSP00000451582.1
	ESR2	ENST00000341099.6	TSL:1 MANE Select	c.1407-4A>G		splice_region intron	N/A	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.1406+1643A>G		intron	N/A	ENSP00000335551.4

Frequencies

GnomAD3 genomes AF: 0.0820 AC: 12468 AN: 152034 Hom.: 1003 Cov.: 31

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.00662

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.0411

Gnomad FIN AF: 0.0936

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.0949 AC: 23740 AN: 250152 AF XY: 0.0847

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.170

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0365

Gnomad OTH exome AF: 0.0644

GnomAD4 exome AF: 0.0519 AC: 75444 AN: 1454360 Hom.: 5381 Cov.: 32 AF XY: 0.0502 AC XY: 36241 AN XY: 721828

African (AFR) AF: 0.110 AC: 3664 AN: 33340

American (AMR) AF: 0.163 AC: 7263 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.0128 AC: 333 AN: 26038

East Asian (EAS) AF: 0.403 AC: 15883 AN: 39460

South Asian (SAS) AF: 0.0299 AC: 2575 AN: 86080

European-Finnish (FIN) AF: 0.0831 AC: 4432 AN: 53352

Middle Eastern (MID) AF: 0.0206 AC: 118 AN: 5740

European-Non Finnish (NFE) AF: 0.0336 AC: 37166 AN: 1105736

Other (OTH) AF: 0.0668 AC: 4010 AN: 60026

GnomAD4 genome AF: 0.0821 AC: 12487 AN: 152152 Hom.: 1003 Cov.: 31 AF XY: 0.0853 AC XY: 6343 AN XY: 74394

African (AFR) AF: 0.110 AC: 4571 AN: 41510

American (AMR) AF: 0.105 AC: 1610 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0121 AC: 42 AN: 3472

East Asian (EAS) AF: 0.456 AC: 2353 AN: 5156

South Asian (SAS) AF: 0.0409 AC: 197 AN: 4818

European-Finnish (FIN) AF: 0.0936 AC: 993 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0374 AC: 2544 AN: 68002

Other (OTH) AF: 0.0794 AC: 168 AN: 2116

Alfa AF: 0.0567 Hom.: 1273

Bravo AF: 0.0888

Asia WGS AF: 0.208 AC: 721 AN: 3478

EpiCase AF: 0.0287

EpiControl AF: 0.0321

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 16553027)

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

ESR2-related disorder Benign:1

Feb 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	7.6
DANN	Benign	0.79
PhyloP100		-0.72
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000046
dbscSNV1_RF	Benign	0.030
SpliceAI score (max)		0.020		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: rs944050; hg19: chr14-64700045; COSMIC: COSV50829124; COSMIC: COSV50829124;