chr6-151808173-G-C

Variant names:

• chr6-151808173-G-C
• rs746432
• NM_000125.4:c.261G>C

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_000125.4(ESR1):​c.261G>C​(p.Ala87Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0791 in 1,584,942 control chromosomes in the GnomAD database, including 5,621 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.069 (492 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5129 hom.)
• Consequence: ESR1 NM_000125.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.103
• Publications: 40 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 6-151808173-G-C is Benign according to our data. Variant chr6-151808173-G-C is described in ClinVar as Benign. ClinVar VariationId is 1180284.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.103 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0901 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.261G>C	p.Ala87Ala	synonymous	Exon 1 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.261G>C	p.Ala87Ala	synonymous	Exon 2 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.261G>C	p.Ala87Ala	synonymous	Exon 2 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.261G>C	p.Ala87Ala	synonymous	Exon 1 of 8	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.261G>C	p.Ala87Ala	synonymous	Exon 1 of 4	ENSP00000384064.1
	ESR1	ENST00000456483.3	TSL:1	c.261G>C	p.Ala87Ala	synonymous	Exon 1 of 5	ENSP00000415934.3

Frequencies

GnomAD3 genomes AF: 0.0688 AC: 10464 AN: 152112 Hom.: 492 Cov.: 33

Gnomad AFR AF: 0.0392

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.000582

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0920

Gnomad OTH AF: 0.0559

GnomAD2 exomes AF: 0.0659 AC: 12699 AN: 192798 AF XY: 0.0656

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.0275

Gnomad ASJ exome AF: 0.0699

Gnomad EAS exome AF: 0.000552

Gnomad FIN exome AF: 0.129

Gnomad NFE exome AF: 0.0910

Gnomad OTH exome AF: 0.0671

GnomAD4 exome AF: 0.0802 AC: 114906 AN: 1432710 Hom.: 5129 Cov.: 37 AF XY: 0.0790 AC XY: 56071 AN XY: 709686

African (AFR) AF: 0.0357 AC: 1174 AN: 32916

American (AMR) AF: 0.0284 AC: 1157 AN: 40754

Ashkenazi Jewish (ASJ) AF: 0.0675 AC: 1721 AN: 25494

East Asian (EAS) AF: 0.000235 AC: 9 AN: 38240

South Asian (SAS) AF: 0.0349 AC: 2884 AN: 82572

European-Finnish (FIN) AF: 0.129 AC: 6459 AN: 50140

Middle Eastern (MID) AF: 0.0284 AC: 162 AN: 5702

European-Non Finnish (NFE) AF: 0.0884 AC: 97021 AN: 1097682

Other (OTH) AF: 0.0729 AC: 4319 AN: 59210

GnomAD4 genome AF: 0.0688 AC: 10467 AN: 152232 Hom.: 492 Cov.: 33 AF XY: 0.0692 AC XY: 5153 AN XY: 74444

African (AFR) AF: 0.0391 AC: 1626 AN: 41572

American (AMR) AF: 0.0331 AC: 507 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.000583 AC: 3 AN: 5146

South Asian (SAS) AF: 0.0373 AC: 180 AN: 4830

European-Finnish (FIN) AF: 0.134 AC: 1426 AN: 10604

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0920 AC: 6253 AN: 67982

Other (OTH) AF: 0.0553 AC: 117 AN: 2116

Alfa AF: 0.0729 Hom.: 163

Bravo AF: 0.0591

Asia WGS AF: 0.0200 AC: 70 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26585143, 28815558, 24607813)

ESR1-related disorder Benign:1

May 31, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.4
DANN	Benign	0.66
PhyloP100		-0.10
PromoterAI		-0.0046	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs746432; hg19: chr6-152129308; COSMIC: COSV52787264; COSMIC: COSV52787264;