NM_000125.4:c.*4142T>C

Variant names:

• chr6-152103108-T-C
• rs3798757
• NM_000125.4:c.*4142T>C

Variant summary

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

The NM_000125.4(ESR1):​c.*4142T>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 0.00629 in 218,392 control chromosomes in the GnomAD database, including 61 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 0.0032 (20 hom., cov: 33)
  • Exomes 𝑓: 0.013 (41 hom.)
• Consequence: ESR1 NM_000125.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.885
• 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=-0.51).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0786 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.*4142T>C		3_prime_UTR	Exon 8 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.*4142T>C		3_prime_UTR	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.*4142T>C		3_prime_UTR	Exon 9 of 9	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.*4142T>C		3_prime_UTR	Exon 8 of 8	ENSP00000206249.3
	ESR1	ENST00000427531.6	TSL:1	c.851-22158T>C		intron	N/A	ENSP00000394721.2
	ESR1	ENST00000440973.5	TSL:5	c.*4142T>C		3_prime_UTR	Exon 10 of 10	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152224 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0856

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.0135 AC: 889 AN: 66050 Hom.: 41 Cov.: 0 AF XY: 0.0140 AC XY: 427 AN XY: 30578

African (AFR) AF: 0.00 AC: 0 AN: 3010

American (AMR) AF: 0.00 AC: 0 AN: 1922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4132

East Asian (EAS) AF: 0.0894 AC: 858 AN: 9594

South Asian (SAS) AF: 0.00351 AC: 2 AN: 570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 418

European-Non Finnish (NFE) AF: 0.000124 AC: 5 AN: 40418

Other (OTH) AF: 0.00435 AC: 24 AN: 5516

GnomAD4 genome AF: 0.00318 AC: 485 AN: 152342 Hom.: 20 Cov.: 33 AF XY: 0.00365 AC XY: 272 AN XY: 74494

African (AFR) AF: 0.0000721 AC: 3 AN: 41584

American (AMR) AF: 0.000327 AC: 5 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0852 AC: 442 AN: 5188

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000517 Hom.: 7

Bravo AF: 0.00337

Asia WGS AF: 0.0320 AC: 112 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	8.5
DANN	Benign	0.61
PhyloP100		0.89
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: rs3798757; hg19: chr6-152424243; COSMIC: COSV106333960; COSMIC: COSV106333960;