chr14-64249055-G-A

Variant names:

• chr14-64249055-G-A
• rs17766755
• NM_001437.3:c.1225+491C>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.1225+491C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.312 in 151,894 control chromosomes in the GnomAD database, including 7,681 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 0.31 (7681 hom., cov: 31)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.483
• Publications: 19 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.355 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.1225+491C>T		intron	N/A	NP_001428.1
	ESR2	NM_001040275.1		c.1225+491C>T		intron	N/A	NP_001035365.1
	ESR2	NM_001291712.2		c.1225+491C>T		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.1225+491C>T		intron	N/A	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.1225+491C>T		intron	N/A	ENSP00000335551.4
	ESR2	ENST00000554572.5	TSL:1	c.1225+491C>T		intron	N/A	ENSP00000450699.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47378 AN: 151776 Hom.: 7686 Cov.: 31

Gnomad AFR AF: 0.264

Gnomad AMI AF: 0.495

Gnomad AMR AF: 0.251

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.129

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.348

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.359

Gnomad OTH AF: 0.314

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

GnomAD4 genome AF: 0.312 AC: 47380 AN: 151894 Hom.: 7681 Cov.: 31 AF XY: 0.308 AC XY: 22894 AN XY: 74218

African (AFR) AF: 0.264 AC: 10937 AN: 41398

American (AMR) AF: 0.251 AC: 3826 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1418 AN: 3462

East Asian (EAS) AF: 0.128 AC: 664 AN: 5168

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4812

European-Finnish (FIN) AF: 0.348 AC: 3663 AN: 10520

Middle Eastern (MID) AF: 0.384 AC: 112 AN: 292

European-Non Finnish (NFE) AF: 0.359 AC: 24361 AN: 67948

Other (OTH) AF: 0.310 AC: 655 AN: 2112

Alfa AF: 0.337 Hom.: 2149

Bravo AF: 0.300

Asia WGS AF: 0.219 AC: 763 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.69
DANN	Benign	0.60
PhyloP100		-0.48
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: rs17766755; hg19: chr14-64715773;