6-151862416-G-A

Variant names:

• chr6-151862416-G-A
• rs1643821
• NM_000125.4:c.644-18239G>A

Variant summary

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

The NM_000125.4(ESR1):​c.644-18239G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 151,982 control chromosomes in the GnomAD database, including 17,004 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 0.46 (17004 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.397
• Publications: 19 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 = 0.613 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.644-18239G>A		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.650-18239G>A		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.644-18239G>A		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.644-18239G>A		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+54052G>A		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.125-18239G>A		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70097 AN: 151864 Hom.: 16972 Cov.: 31

Gnomad AFR AF: 0.619

Gnomad AMI AF: 0.378

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.473

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.451

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

GnomAD4 genome AF: 0.462 AC: 70181 AN: 151982 Hom.: 17004 Cov.: 31 AF XY: 0.454 AC XY: 33709 AN XY: 74258

African (AFR) AF: 0.620 AC: 25695 AN: 41462

American (AMR) AF: 0.373 AC: 5688 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 1640 AN: 3470

East Asian (EAS) AF: 0.464 AC: 2387 AN: 5142

South Asian (SAS) AF: 0.424 AC: 2043 AN: 4816

European-Finnish (FIN) AF: 0.311 AC: 3281 AN: 10564

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 28020 AN: 67966

Other (OTH) AF: 0.454 AC: 954 AN: 2100

Alfa AF: 0.430 Hom.: 55186

Bravo AF: 0.472

Asia WGS AF: 0.476 AC: 1656 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.58
DANN	Benign	0.54
PhyloP100		-0.40
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: rs1643821; hg19: chr6-152183551; COSMIC: COSV52800743;