6-151944387-G-C

Variant names:

• chr6-151944387-G-C
• rs1801132
• NM_000125.4:c.975G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_000125.4(ESR1):​c.975G>C​(p.Pro325Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.755 in 1,613,900 control chromosomes in the GnomAD database, including 464,431 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 0.79 (47934 hom., cov: 31)
  • Exomes 𝑓: 0.75 (416497 hom.)
• Consequence: ESR1 NM_000125.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.11
• Publications: 181 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.004).
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.975G>C	p.Pro325Pro	synonymous_variant	Exon 4 of 8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.975G>C	p.Pro325Pro	synonymous_variant	Exon 4 of 8	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.789 AC: 119880 AN: 151994 Hom.: 47896 Cov.: 31

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.798

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.725

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.777

Gnomad OTH AF: 0.795

GnomAD2 exomes AF: 0.730 AC: 183513 AN: 251348 AF XY: 0.726

Gnomad AFR exome AF: 0.901

Gnomad AMR exome AF: 0.692

Gnomad ASJ exome AF: 0.794

Gnomad EAS exome AF: 0.508

Gnomad FIN exome AF: 0.736

Gnomad NFE exome AF: 0.779

Gnomad OTH exome AF: 0.747

GnomAD4 exome AF: 0.752 AC: 1098715 AN: 1461788 Hom.: 416497 Cov.: 56 AF XY: 0.748 AC XY: 543763 AN XY: 727202

African (AFR) AF: 0.907 AC: 30361 AN: 33480

American (AMR) AF: 0.696 AC: 31130 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.801 AC: 20937 AN: 26136

East Asian (EAS) AF: 0.501 AC: 19906 AN: 39700

South Asian (SAS) AF: 0.607 AC: 52325 AN: 86258

European-Finnish (FIN) AF: 0.736 AC: 39307 AN: 53420

Middle Eastern (MID) AF: 0.749 AC: 4318 AN: 5768

European-Non Finnish (NFE) AF: 0.769 AC: 855367 AN: 1111910

Other (OTH) AF: 0.746 AC: 45064 AN: 60394

GnomAD4 genome AF: 0.789 AC: 119972 AN: 152112 Hom.: 47934 Cov.: 31 AF XY: 0.780 AC XY: 57999 AN XY: 74330

African (AFR) AF: 0.897 AC: 37260 AN: 41522

American (AMR) AF: 0.744 AC: 11370 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.798 AC: 2771 AN: 3472

East Asian (EAS) AF: 0.497 AC: 2553 AN: 5138

South Asian (SAS) AF: 0.592 AC: 2851 AN: 4818

European-Finnish (FIN) AF: 0.725 AC: 7650 AN: 10558

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.777 AC: 52838 AN: 68010

Other (OTH) AF: 0.791 AC: 1664 AN: 2104

Alfa AF: 0.774 Hom.: 11902

Bravo AF: 0.796

Asia WGS AF: 0.584 AC: 2035 AN: 3478

EpiCase AF: 0.777

EpiControl AF: 0.773

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.2
DANN	Benign	0.46
PhyloP100		-1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1801132; hg19: chr6-152265522; COSMIC: COSV52791570;