NM_001437.3:c.1225+3909T>C

Variant names:

• chr14-64245637-A-G
• rs1952585
• NM_001437.3:c.1225+3909T>C

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+3909T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 151,856 control chromosomes in the GnomAD database, including 6,439 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 0.22 (6439 hom., cov: 31)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.452
• Publications: 6 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 = 0.514 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+3909T>C		intron	N/A	NP_001428.1
	ESR2	NM_001040275.1		c.1225+3909T>C		intron	N/A	NP_001035365.1
	ESR2	NM_001291712.2		c.1225+3909T>C		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+3909T>C		intron	N/A	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.1225+3909T>C		intron	N/A	ENSP00000335551.4
	ESR2	ENST00000554572.5	TSL:1	c.1225+3909T>C		intron	N/A	ENSP00000450699.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33412 AN: 151742 Hom.: 6421 Cov.: 31

Gnomad AFR AF: 0.520

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.202

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.0392

Gnomad MID AF: 0.135

Gnomad NFE AF: 0.0831

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.220 AC: 33473 AN: 151856 Hom.: 6439 Cov.: 31 AF XY: 0.217 AC XY: 16097 AN XY: 74204

African (AFR) AF: 0.520 AC: 21524 AN: 41368

American (AMR) AF: 0.202 AC: 3081 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 501 AN: 3470

East Asian (EAS) AF: 0.181 AC: 936 AN: 5172

South Asian (SAS) AF: 0.149 AC: 715 AN: 4804

European-Finnish (FIN) AF: 0.0392 AC: 413 AN: 10538

Middle Eastern (MID) AF: 0.138 AC: 40 AN: 290

European-Non Finnish (NFE) AF: 0.0831 AC: 5650 AN: 67954

Other (OTH) AF: 0.213 AC: 448 AN: 2106

Alfa AF: 0.153 Hom.: 761

Bravo AF: 0.249

Asia WGS AF: 0.169 AC: 587 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	0.20
DANN	Benign	0.31
PhyloP100		-0.45
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: rs1952585; hg19: chr14-64712355;