6-151880740-T-C

Variant names:

• chr6-151880740-T-C
• rs4986934
• NM_000125.4:c.729T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_000125.4(ESR1):​c.729T>C​(p.Arg243Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.963 in 1,609,552 control chromosomes in the GnomAD database, including 746,158 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 0.97 (72147 hom., cov: 33)
  • Exomes 𝑓: 0.96 (674011 hom.)
• Consequence: ESR1 NM_000125.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.124
• Publications: 43 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.082).
• BP7: Synonymous conserved (PhyloP=0.124 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.729T>C	p.Arg243Arg	synonymous_variant	Exon 3 of 8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.729T>C	p.Arg243Arg	synonymous_variant	Exon 3 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.973 AC: 148111 AN: 152238 Hom.: 72087 Cov.: 33

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.979

Gnomad ASJ AF: 0.941

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.977

Gnomad FIN AF: 0.956

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.960

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.970 AC: 243858 AN: 251378 AF XY: 0.970

Gnomad AFR exome AF: 0.994

Gnomad AMR exome AF: 0.978

Gnomad ASJ exome AF: 0.940

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.959

Gnomad NFE exome AF: 0.962

Gnomad OTH exome AF: 0.968

GnomAD4 exome AF: 0.962 AC: 1401412 AN: 1457196 Hom.: 674011 Cov.: 33 AF XY: 0.962 AC XY: 697957 AN XY: 725372

African (AFR) AF: 0.995 AC: 33219 AN: 33398

American (AMR) AF: 0.978 AC: 43712 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.940 AC: 24551 AN: 26106

East Asian (EAS) AF: 0.999 AC: 39653 AN: 39674

South Asian (SAS) AF: 0.977 AC: 84190 AN: 86156

European-Finnish (FIN) AF: 0.960 AC: 51260 AN: 53406

Middle Eastern (MID) AF: 0.982 AC: 5656 AN: 5760

European-Non Finnish (NFE) AF: 0.958 AC: 1061036 AN: 1107732

Other (OTH) AF: 0.965 AC: 58135 AN: 60246

GnomAD4 genome AF: 0.973 AC: 148230 AN: 152356 Hom.: 72147 Cov.: 33 AF XY: 0.973 AC XY: 72440 AN XY: 74482

African (AFR) AF: 0.994 AC: 41320 AN: 41588

American (AMR) AF: 0.979 AC: 14993 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 3267 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5178

South Asian (SAS) AF: 0.977 AC: 4721 AN: 4832

European-Finnish (FIN) AF: 0.956 AC: 10143 AN: 10612

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 0.960 AC: 65339 AN: 68040

Other (OTH) AF: 0.977 AC: 2067 AN: 2116

Alfa AF: 0.964 Hom.: 83066

Bravo AF: 0.976

Asia WGS AF: 0.990 AC: 3441 AN: 3478

EpiCase AF: 0.964

EpiControl AF: 0.964

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	12
DANN	Benign	0.72
PhyloP100		0.12
PromoterAI		0.039	Neutral
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs4986934; hg19: chr6-152201875; COSMIC: COSV108024177;