NM_001437.3:c.535+1574G>A

Variant names:

• chr14-64278407-C-T
• rs1256034
• NM_001437.3:c.535+1574G>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.535+1574G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0458 in 152,216 control chromosomes in the GnomAD database, including 521 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 0.046 (521 hom., cov: 32)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• Publications: 7 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 (EAS) allele frequency at 95% confidence interval = 0.357 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	NM_001437.3	MANE Select	c.535+1574G>A		intron	N/A	NP_001428.1	Q92731-1
	ESR2	NM_001040275.1		c.535+1574G>A		intron	N/A	NP_001035365.1	Q92731-2
	ESR2	NM_001291712.2		c.535+1574G>A		intron	N/A	NP_001278641.1	Q92731-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000341099.6	TSL:1 MANE Select	c.535+1574G>A		intron	N/A	ENSP00000343925.4	Q92731-1
	ESR2	ENST00000353772.7	TSL:1	c.535+1574G>A		intron	N/A	ENSP00000335551.4	Q92731-2
	ESR2	ENST00000554572.5	TSL:1	c.535+1574G>A		intron	N/A	ENSP00000450699.1	Q92731-2

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6964 AN: 152098 Hom.: 522 Cov.: 32

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0387

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.0382

Gnomad FIN AF: 0.0882

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0372

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

GnomAD4 genome AF: 0.0458 AC: 6975 AN: 152216 Hom.: 521 Cov.: 32 AF XY: 0.0497 AC XY: 3699 AN XY: 74424

African (AFR) AF: 0.0159 AC: 660 AN: 41536

American (AMR) AF: 0.0387 AC: 591 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3468

East Asian (EAS) AF: 0.371 AC: 1921 AN: 5176

South Asian (SAS) AF: 0.0382 AC: 184 AN: 4818

European-Finnish (FIN) AF: 0.0882 AC: 935 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2554 AN: 68010

Other (OTH) AF: 0.0397 AC: 84 AN: 2116

Alfa AF: 0.0463 Hom.: 647

Bravo AF: 0.0412

Asia WGS AF: 0.170 AC: 588 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	0.95
DANN	Benign	0.34
PhyloP100		-0.15
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: rs1256034; hg19: chr14-64745125;