6-152068864-A-G

Variant names:

• chr6-152068864-A-G
• rs3020376
• NM_000125.4:c.1369+7740A>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.1369+7740A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 110,150 control chromosomes in the GnomAD database, including 11,839 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 0.39 (11839 hom., cov: 27)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.227
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.685 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1369+7740A>G		intron_variant	Intron 6 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1369+7740A>G		intron_variant	Intron 6 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.385 AC: 42389 AN: 110078 Hom.: 11811 Cov.: 27

Gnomad AFR AF: 0.693

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.229

Gnomad EAS AF: 0.511

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.392

Gnomad MID AF: 0.281

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.385 AC: 42454 AN: 110150 Hom.: 11839 Cov.: 27 AF XY: 0.388 AC XY: 20784 AN XY: 53604

African (AFR) AF: 0.694 AC: 14812 AN: 21340

American (AMR) AF: 0.207 AC: 2602 AN: 12550

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 656 AN: 2864

East Asian (EAS) AF: 0.510 AC: 1409 AN: 2764

South Asian (SAS) AF: 0.557 AC: 2037 AN: 3658

European-Finnish (FIN) AF: 0.392 AC: 2995 AN: 7648

Middle Eastern (MID) AF: 0.291 AC: 68 AN: 234

European-Non Finnish (NFE) AF: 0.302 AC: 17150 AN: 56874

Other (OTH) AF: 0.334 AC: 495 AN: 1480

Alfa AF: 0.297 Hom.: 1656

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.54
DANN	Benign	0.41
PhyloP100		-0.23
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: rs3020376; hg19: chr6-152389999;