6-151831853-A-G

Variant names:

• chr6-151831853-A-G
• rs6926750
• NM_000125.4:c.453-10744A>G

Variant summary

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

The NM_000125.4(ESR1):​c.453-10744A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.288 in 151,998 control chromosomes in the GnomAD database, including 9,342 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 0.29 (9342 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.603 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.453-10744A>G		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.453-10744A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.453-10744A>G		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.453-10744A>G		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+23489A>G		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.-67-10744A>G		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.288 AC: 43754 AN: 151880 Hom.: 9305 Cov.: 32

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.173

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.157

Gnomad OTH AF: 0.237

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.288 AC: 43844 AN: 151998 Hom.: 9342 Cov.: 32 AF XY: 0.286 AC XY: 21227 AN XY: 74306

African (AFR) AF: 0.609 AC: 25245 AN: 41440

American (AMR) AF: 0.146 AC: 2224 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3466

East Asian (EAS) AF: 0.291 AC: 1500 AN: 5158

South Asian (SAS) AF: 0.238 AC: 1144 AN: 4810

European-Finnish (FIN) AF: 0.173 AC: 1826 AN: 10584

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.157 AC: 10651 AN: 67962

Other (OTH) AF: 0.244 AC: 513 AN: 2106

Alfa AF: 0.131 Hom.: 328

Bravo AF: 0.297

Asia WGS AF: 0.299 AC: 1038 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.4
DANN	Benign	0.53
PhyloP100		-0.21
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: rs6926750; hg19: chr6-152152988;