rs1256063

Variant names:

• chr14-64235499-A-G
• rs1256063
• NM_001437.3:c.1226-349T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-64235499-A-G
• chr14-64235499-A-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.1226-349T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 152,346 control chromosomes in the GnomAD database, including 69,212 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 0.95 (69212 hom., cov: 33)
• Consequence: ESR2 NM_001437.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.483
• Publications: 14 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR2	NM_001437.3	c.1226-349T>C		intron_variant	Intron 7 of 8	ENST00000341099.6	NP_001428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR2	ENST00000341099.6	c.1226-349T>C		intron_variant	Intron 7 of 8	1	NM_001437.3	ENSP00000343925.4

Frequencies

GnomAD3 genomes AF: 0.953 AC: 145029 AN: 152228 Hom.: 69152 Cov.: 33

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.933

Gnomad AMR AF: 0.955

Gnomad ASJ AF: 0.964

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.989

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.924

Gnomad OTH AF: 0.958

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

GnomAD4 genome AF: 0.953 AC: 145148 AN: 152346 Hom.: 69212 Cov.: 33 AF XY: 0.955 AC XY: 71131 AN XY: 74492

African (AFR) AF: 0.988 AC: 41078 AN: 41594

American (AMR) AF: 0.955 AC: 14627 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.964 AC: 3346 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5178

South Asian (SAS) AF: 0.989 AC: 4778 AN: 4830

European-Finnish (FIN) AF: 0.956 AC: 10149 AN: 10616

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.924 AC: 62830 AN: 68028

Other (OTH) AF: 0.959 AC: 2027 AN: 2114

Alfa AF: 0.933 Hom.: 34148

Bravo AF: 0.954

Asia WGS AF: 0.991 AC: 3445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.9
DANN	Benign	0.47
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: rs1256063; hg19: chr14-64702217;