NM_000125.4:c.*584C>G

Variant names:

• chr6-152099550-C-G
• rs33986155
• NM_000125.4:c.*584C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000125.4(ESR1):​c.*584C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0369 in 242,100 control chromosomes in the GnomAD database, including 204 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 0.034 (104 hom., cov: 32)
  • Exomes 𝑓: 0.042 (100 hom.)
• Consequence: ESR1 NM_000125.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.359
• Publications: 5 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=-0.59).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0337 (5126/152208) while in subpopulation NFE AF = 0.0487 (3311/68006). AF 95% confidence interval is 0.0473. There are 104 homozygotes in GnomAd4. There are 2414 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 104 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. 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
	ESR1	NM_000125.4	MANE Select	c.*584C>G		3_prime_UTR	Exon 8 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.*584C>G		3_prime_UTR	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.*584C>G		3_prime_UTR	Exon 9 of 9	NP_001116212.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.*584C>G		3_prime_UTR	Exon 8 of 8	ENSP00000206249.3
	ESR1	ENST00000427531.6	TSL:1	c.851-25716C>G		intron	N/A	ENSP00000394721.2
	ESR1	ENST00000440973.5	TSL:5	c.*584C>G		3_prime_UTR	Exon 10 of 10	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5131 AN: 152090 Hom.: 104 Cov.: 32

Gnomad AFR AF: 0.00927

Gnomad AMI AF: 0.0231

Gnomad AMR AF: 0.0371

Gnomad ASJ AF: 0.0948

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0243

Gnomad FIN AF: 0.0273

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0487

Gnomad OTH AF: 0.0464

GnomAD4 exome AF: 0.0424 AC: 3808 AN: 89892 Hom.: 100 Cov.: 0 AF XY: 0.0432 AC XY: 1809 AN XY: 41832

African (AFR) AF: 0.0104 AC: 42 AN: 4054

American (AMR) AF: 0.0346 AC: 145 AN: 4194

Ashkenazi Jewish (ASJ) AF: 0.0874 AC: 455 AN: 5208

East Asian (EAS) AF: 0.0000847 AC: 1 AN: 11806

South Asian (SAS) AF: 0.0289 AC: 41 AN: 1420

European-Finnish (FIN) AF: 0.0235 AC: 7 AN: 298

Middle Eastern (MID) AF: 0.0534 AC: 27 AN: 506

European-Non Finnish (NFE) AF: 0.0500 AC: 2763 AN: 55284

Other (OTH) AF: 0.0459 AC: 327 AN: 7122

GnomAD4 genome AF: 0.0337 AC: 5126 AN: 152208 Hom.: 104 Cov.: 32 AF XY: 0.0324 AC XY: 2414 AN XY: 74432

African (AFR) AF: 0.00922 AC: 383 AN: 41524

American (AMR) AF: 0.0371 AC: 567 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0948 AC: 329 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0241 AC: 116 AN: 4818

European-Finnish (FIN) AF: 0.0273 AC: 289 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0487 AC: 3311 AN: 68006

Other (OTH) AF: 0.0454 AC: 96 AN: 2114

Alfa AF: 0.0169 Hom.: 5

Bravo AF: 0.0335

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	5.3
DANN	Benign	0.76
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism

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: rs33986155; hg19: chr6-152420685;