14-64227477-C-T

Variant names:

• chr14-64227477-C-T
• rs928554
• ENST00000353772.7:c.*56G>A

Variant summary

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

The NM_001040275.1(ESR2):​c.*56G>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 0.579 in 1,567,086 control chromosomes in the GnomAD database, including 268,171 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (34506 hom., cov: 33)
  • Exomes 𝑓: 0.57 (233665 hom.)
• Consequence: ESR2 NM_001040275.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.441
• Publications: 56 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=-0.92).
• BP6: Variant 14-64227477-C-T is Benign according to our data. Variant chr14-64227477-C-T is described in ClinVar as Benign. ClinVar VariationId is 1286246.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.872 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040275.1. 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_001040275.1		c.*56G>A		3_prime_UTR	Exon 9 of 9	NP_001035365.1	Q92731-2
	ESR2	NM_001291712.2		c.*56G>A		3_prime_UTR	Exon 14 of 14	NP_001278641.1	Q92731-2
	ESR2	NM_001291723.1		c.*56G>A		3_prime_UTR	Exon 9 of 9	NP_001278652.1	Q92731-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR2	ENST00000353772.7	TSL:1	c.*56G>A		3_prime_UTR	Exon 9 of 9	ENSP00000335551.4	Q92731-2
	ESR2	ENST00000554572.5	TSL:1	c.*56G>A		3_prime_UTR	Exon 14 of 14	ENSP00000450699.1	Q92731-2
	ESR2	ENST00000555278.5	TSL:1	c.*413G>A		3_prime_UTR	Exon 8 of 8	ENSP00000450488.1	Q92731-5

Frequencies

GnomAD3 genomes AF: 0.658 AC: 100031 AN: 152048 Hom.: 34453 Cov.: 33

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.782

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.505

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.573

Gnomad NFE AF: 0.566

Gnomad OTH AF: 0.639

GnomAD4 exome AF: 0.571 AC: 807400 AN: 1414920 Hom.: 233665 Cov.: 22 AF XY: 0.568 AC XY: 400773 AN XY: 705992

African (AFR) AF: 0.892 AC: 28611 AN: 32090

American (AMR) AF: 0.531 AC: 22704 AN: 42726

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 16461 AN: 25650

East Asian (EAS) AF: 0.642 AC: 25283 AN: 39380

South Asian (SAS) AF: 0.501 AC: 41736 AN: 83292

European-Finnish (FIN) AF: 0.560 AC: 29821 AN: 53212

Middle Eastern (MID) AF: 0.594 AC: 3358 AN: 5654

European-Non Finnish (NFE) AF: 0.563 AC: 604446 AN: 1074154

Other (OTH) AF: 0.595 AC: 34980 AN: 58762

GnomAD4 genome AF: 0.658 AC: 100139 AN: 152166 Hom.: 34506 Cov.: 33 AF XY: 0.653 AC XY: 48608 AN XY: 74394

African (AFR) AF: 0.880 AC: 36544 AN: 41536

American (AMR) AF: 0.561 AC: 8574 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.641 AC: 2223 AN: 3470

East Asian (EAS) AF: 0.694 AC: 3594 AN: 5180

South Asian (SAS) AF: 0.505 AC: 2435 AN: 4826

European-Finnish (FIN) AF: 0.573 AC: 6056 AN: 10564

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.566 AC: 38491 AN: 67984

Other (OTH) AF: 0.638 AC: 1347 AN: 2110

Alfa AF: 0.629 Hom.: 24021

Bravo AF: 0.671

Asia WGS AF: 0.612 AC: 2127 AN: 3478

ClinVar

ClinVar submissions

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	-0.92
CADD	Benign	0.34
DANN	Benign	0.65
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs928554; hg19: chr14-64694195; COSMIC: COSV59952189; COSMIC: COSV59952189;