14-64294095-AG-AGG

Variant names:

• chr14-64294095-A-AG
• rs3832949
• NM_001437.3:c.-154dupC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001437.3(ESR2):​c.-154dupC variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 152,378 control chromosomes in the GnomAD database, including 81 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.018 (81 hom., cov: 33)
  • Exomes 𝑓: 0.021 (0 hom.)
• Consequence: ESR2 NM_001437.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0890
• Publications: 4 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0884 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.-154dupC		5_prime_UTR	Exon 1 of 9	NP_001428.1
	ESR2	NM_001040275.1		c.-154dupC		5_prime_UTR	Exon 1 of 9	NP_001035365.1
	ESR2	NM_001291712.2		c.-91+3437dupC		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.-154dupC		5_prime_UTR	Exon 1 of 9	ENSP00000343925.4
	ESR2	ENST00000353772.7	TSL:1	c.-154dupC		5_prime_UTR	Exon 1 of 9	ENSP00000335551.4
	ESR2	ENST00000554572.5	TSL:1	c.-91+3437dupC		intron	N/A	ENSP00000450699.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2801 AN: 152168 Hom.: 80 Cov.: 33

Gnomad AFR AF: 0.0254

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0609

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0954

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00215

Gnomad OTH AF: 0.0307

GnomAD4 exome AF: 0.0213 AC: 2 AN: 94 Hom.: 0 Cov.: 0 AF XY: 0.0147 AC XY: 1 AN XY: 68

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 80

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.0185 AC: 2812 AN: 152284 Hom.: 81 Cov.: 33 AF XY: 0.0193 AC XY: 1438 AN XY: 74466

African (AFR) AF: 0.0255 AC: 1059 AN: 41566

American (AMR) AF: 0.0612 AC: 937 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.0954 AC: 493 AN: 5168

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4828

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00215 AC: 146 AN: 68012

Other (OTH) AF: 0.0313 AC: 66 AN: 2110

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.0265

Asia WGS AF: 0.0560 AC: 195 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.089
Mutation Taster		=300/0	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: rs3832949; hg19: chr14-64760813;