chr6-152099995-T-C

Variant names:

• chr6-152099995-T-C
• rs3798577
• NM_000125.4:c.*1029T>C

Variant summary

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

The NM_001291230.2(ESR1):​c.*1029T>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 0.456 in 398,584 control chromosomes in the GnomAD database, including 41,644 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 0.45 (15622 hom., cov: 33)
  • Exomes 𝑓: 0.46 (26022 hom.)
• Consequence: ESR1 NM_001291230.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 116 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=-0.83).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291230.2. 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.*1029T>C		3_prime_UTR	Exon 8 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.*1029T>C		3_prime_UTR	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.*1029T>C		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.*1029T>C		3_prime_UTR	Exon 8 of 8	ENSP00000206249.3
	ESR1	ENST00000427531.6	TSL:1	c.851-25271T>C		intron	N/A	ENSP00000394721.2
	ESR1	ENST00000440973.5	TSL:5	c.*1029T>C		3_prime_UTR	Exon 10 of 10	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.454 AC: 68935 AN: 151978 Hom.: 15623 Cov.: 33

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.460

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.409

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.472

Gnomad OTH AF: 0.452

GnomAD4 exome AF: 0.458 AC: 112769 AN: 246488 Hom.: 26022 Cov.: 0 AF XY: 0.458 AC XY: 57250 AN XY: 124940

African (AFR) AF: 0.431 AC: 3096 AN: 7184

American (AMR) AF: 0.436 AC: 3240 AN: 7438

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 4036 AN: 9242

East Asian (EAS) AF: 0.417 AC: 9548 AN: 22892

South Asian (SAS) AF: 0.528 AC: 1604 AN: 3036

European-Finnish (FIN) AF: 0.431 AC: 8970 AN: 20830

Middle Eastern (MID) AF: 0.447 AC: 579 AN: 1294

European-Non Finnish (NFE) AF: 0.469 AC: 74199 AN: 158196

Other (OTH) AF: 0.458 AC: 7497 AN: 16376

GnomAD4 genome AF: 0.453 AC: 68972 AN: 152096 Hom.: 15622 Cov.: 33 AF XY: 0.454 AC XY: 33773 AN XY: 74354

African (AFR) AF: 0.430 AC: 17834 AN: 41480

American (AMR) AF: 0.460 AC: 7042 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1525 AN: 3470

East Asian (EAS) AF: 0.425 AC: 2189 AN: 5154

South Asian (SAS) AF: 0.520 AC: 2511 AN: 4828

European-Finnish (FIN) AF: 0.409 AC: 4325 AN: 10586

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.472 AC: 32061 AN: 67956

Other (OTH) AF: 0.455 AC: 961 AN: 2114

Alfa AF: 0.467 Hom.: 19396

Bravo AF: 0.454

Asia WGS AF: 0.479 AC: 1665 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.66
DANN	Benign	0.80
PhyloP100		-0.11
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: rs3798577; hg19: chr6-152421130; COSMIC: COSV52805170;