rs2982572

Variant names:

• chr6-151689426-C-T
• rs2982572
• ENST00000473497.5:n.74-12449C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000473497.5(ESR1):​n.74-12449C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.389 in 152,026 control chromosomes in the GnomAD database, including 11,860 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 0.39 (11860 hom., cov: 33)
• Consequence: ESR1 ENST00000473497.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 4 publications found

Genes affected

ESR1 (HGNC:3467): (estrogen receptor 1) This gene encodes an estrogen receptor and ligand-activated transcription factor. The canonical protein contains an N-terminal ligand-independent transactivation domain, a central DNA binding domain, a hinge domain, and a C-terminal ligand-dependent transactivation domain. The protein localizes to the nucleus where it may form either a homodimer or a heterodimer with estrogen receptor 2. The protein encoded by this gene regulates the transcription of many estrogen-inducible genes that play a role in growth, metabolism, sexual development, gestation, and other reproductive functions and is expressed in many non-reproductive tissues. The receptor encoded by this gene plays a key role in breast cancer, endometrial cancer, and osteoporosis. This gene is reported to have dozens of transcript variants due to the use of alternate promoters and alternative splicing, however, the full-length nature of many of these variants remain uncertain. [provided by RefSeq, Jul 2020]

ESR1 Gene-Disease associations (from GenCC):

• estrogen resistance syndrome

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001385568.1	c.-201-12449C>T		intron_variant	Intron 1 of 9		NP_001372497.1
ESR1	XM_017010377.2	c.-201-12449C>T		intron_variant	Intron 2 of 10		XP_016865866.1
ESR1	XM_017010380.2	c.-71+32663C>T		intron_variant	Intron 1 of 8		XP_016865869.1
ESR1	XM_047418290.1	c.-201-12449C>T		intron_variant	Intron 1 of 9		XP_047274246.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000473497.5	n.74-12449C>T		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes AF: 0.389 AC: 59123 AN: 151906 Hom.: 11858 Cov.: 33

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.135

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.365

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

GnomAD4 genome AF: 0.389 AC: 59149 AN: 152026 Hom.: 11860 Cov.: 33 AF XY: 0.384 AC XY: 28524 AN XY: 74294

African (AFR) AF: 0.367 AC: 15207 AN: 41452

American (AMR) AF: 0.365 AC: 5580 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1266 AN: 3466

East Asian (EAS) AF: 0.135 AC: 698 AN: 5172

South Asian (SAS) AF: 0.226 AC: 1092 AN: 4832

European-Finnish (FIN) AF: 0.457 AC: 4820 AN: 10536

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.428 AC: 29118 AN: 67968

Other (OTH) AF: 0.361 AC: 763 AN: 2114

Alfa AF: 0.413 Hom.: 6874

Bravo AF: 0.380

Asia WGS AF: 0.191 AC: 669 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.76
PhyloP100		-0.22

Splicing

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

Other links and lift over

dbSNP: rs2982572; hg19: chr6-152010561; COSMIC: COSV68604081;