chr14-64233098-C-T

Variant names:

• chr14-64233098-C-T
• rs4986938
• NM_001437.3:c.*39G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001437.3(ESR2):​c.*39G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,594,296 control chromosomes in the GnomAD database, including 102,226 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8374 hom., cov: 31)
  • Exomes 𝑓: 0.35 (93852 hom.)
• Consequence: ESR2 NM_001437.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.222
• Publications: 247 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)

LOC124903328 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 14-64233098-C-T is Benign according to our data. Variant chr14-64233098-C-T is described in ClinVar as Benign. ClinVar VariationId is 1266011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.371 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.*39G>A		3_prime_UTR	Exon 9 of 9	NP_001428.1
	ESR2	NM_001271877.1		c.*39G>A		3_prime_UTR	Exon 6 of 6	NP_001258806.1
	ESR2	NM_001040275.1		c.1406+1872G>A		intron	N/A	NP_001035365.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000341099.6	TSL:1 MANE Select	c.*39G>A		3_prime_UTR	Exon 9 of 9	ENSP00000343925.4
	ESR2	ENST00000557772.5	TSL:1	c.*1859G>A		3_prime_UTR	Exon 7 of 7	ENSP00000451582.1
	ESR2	ENST00000267525.10	TSL:1	c.*39G>A		3_prime_UTR	Exon 6 of 6	ENSP00000267525.6

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49115 AN: 151878 Hom.: 8380 Cov.: 31

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.615

Gnomad AMR AF: 0.267

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.332

GnomAD2 exomes AF: 0.310 AC: 75935 AN: 244898 AF XY: 0.318

Gnomad AFR exome AF: 0.257

Gnomad AMR exome AF: 0.176

Gnomad ASJ exome AF: 0.422

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.361

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.355 AC: 511822 AN: 1442300 Hom.: 93852 Cov.: 34 AF XY: 0.354 AC XY: 252570 AN XY: 714176

African (AFR) AF: 0.260 AC: 8599 AN: 33106

American (AMR) AF: 0.186 AC: 8187 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 10658 AN: 25402

East Asian (EAS) AF: 0.134 AC: 5267 AN: 39272

South Asian (SAS) AF: 0.294 AC: 24958 AN: 84810

European-Finnish (FIN) AF: 0.356 AC: 18858 AN: 52912

Middle Eastern (MID) AF: 0.411 AC: 2038 AN: 4954

European-Non Finnish (NFE) AF: 0.375 AC: 412372 AN: 1098488

Other (OTH) AF: 0.352 AC: 20885 AN: 59406

GnomAD4 genome AF: 0.323 AC: 49123 AN: 151996 Hom.: 8374 Cov.: 31 AF XY: 0.320 AC XY: 23803 AN XY: 74306

African (AFR) AF: 0.262 AC: 10879 AN: 41444

American (AMR) AF: 0.267 AC: 4078 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 1482 AN: 3468

East Asian (EAS) AF: 0.123 AC: 638 AN: 5172

South Asian (SAS) AF: 0.291 AC: 1400 AN: 4806

European-Finnish (FIN) AF: 0.360 AC: 3797 AN: 10560

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.375 AC: 25484 AN: 67952

Other (OTH) AF: 0.327 AC: 691 AN: 2110

Alfa AF: 0.355 Hom.: 31277

Bravo AF: 0.312

Asia WGS AF: 0.232 AC: 809 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.73
PhyloP100		-0.22
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: rs4986938; hg19: chr14-64699816; COSMIC: COSV50828487; COSMIC: COSV50828487;