NM_000125.4:c.*3027T>C

Variant names:

• chr6-152101993-T-C
• rs9341077
• NM_000125.4:c.*3027T>C

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.*3027T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0342 in 214,488 control chromosomes in the GnomAD database, including 150 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 (94 hom., cov: 32)
  • Exomes 𝑓: 0.035 (56 hom.)
• Consequence: ESR1 NM_000125.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.300
• Publications: 15 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=-0.84).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0339 (5160/152254) while in subpopulation AMR AF = 0.0481 (736/15298). AF 95% confidence interval is 0.0452. There are 94 homozygotes in GnomAd4. There are 2464 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 94 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.*3027T>C		3_prime_UTR_variant	Exon 8 of 8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.*3027T>C		3_prime_UTR_variant	Exon 8 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.0339 AC: 5155 AN: 152136 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.0276

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0483

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0370

Gnomad OTH AF: 0.0530

GnomAD4 exome AF: 0.0349 AC: 2170 AN: 62234 Hom.: 56 Cov.: 0 AF XY: 0.0358 AC XY: 1035 AN XY: 28902

African (AFR) AF: 0.0247 AC: 69 AN: 2790

American (AMR) AF: 0.0394 AC: 71 AN: 1800

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 182 AN: 3974

East Asian (EAS) AF: 0.000217 AC: 2 AN: 9204

South Asian (SAS) AF: 0.00564 AC: 3 AN: 532

European-Finnish (FIN) AF: 0.0404 AC: 19 AN: 470

Middle Eastern (MID) AF: 0.0511 AC: 19 AN: 372

European-Non Finnish (NFE) AF: 0.0420 AC: 1594 AN: 37958

Other (OTH) AF: 0.0411 AC: 211 AN: 5134

GnomAD4 genome AF: 0.0339 AC: 5160 AN: 152254 Hom.: 94 Cov.: 32 AF XY: 0.0331 AC XY: 2464 AN XY: 74430

African (AFR) AF: 0.0276 AC: 1146 AN: 41546

American (AMR) AF: 0.0481 AC: 736 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0441 AC: 153 AN: 3466

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.0131 AC: 63 AN: 4822

European-Finnish (FIN) AF: 0.0364 AC: 386 AN: 10606

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0370 AC: 2514 AN: 68012

Other (OTH) AF: 0.0529 AC: 112 AN: 2116

Alfa AF: 0.0362 Hom.: 77

Bravo AF: 0.0338

Asia WGS AF: 0.0120 AC: 43 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.68
DANN	Benign	0.65
PhyloP100		-0.30
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: rs9341077; hg19: chr6-152423128; COSMIC: COSV52785508; COSMIC: COSV52785508;