chr6-152086991-G-A

Variant names:

• chr6-152086991-G-A
• rs750686
• NM_000125.4:c.1370-7394G>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.1370-7394G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 151,988 control chromosomes in the GnomAD database, including 15,301 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 0.43 (15301 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.369
• Publications: 12 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 = 0.599 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.1370-7394G>A		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1376-7394G>A		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1370-7394G>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.1370-7394G>A		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.587-7394G>A		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.850+25867G>A		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.427 AC: 64886 AN: 151870 Hom.: 15262 Cov.: 32

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.253

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.583

Gnomad FIN AF: 0.453

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.342

Gnomad OTH AF: 0.396

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

GnomAD4 genome AF: 0.428 AC: 64985 AN: 151988 Hom.: 15301 Cov.: 32 AF XY: 0.431 AC XY: 32035 AN XY: 74278

African (AFR) AF: 0.605 AC: 25063 AN: 41434

American (AMR) AF: 0.253 AC: 3858 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 982 AN: 3472

East Asian (EAS) AF: 0.586 AC: 3018 AN: 5152

South Asian (SAS) AF: 0.582 AC: 2804 AN: 4820

European-Finnish (FIN) AF: 0.453 AC: 4773 AN: 10544

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.342 AC: 23218 AN: 67978

Other (OTH) AF: 0.400 AC: 843 AN: 2108

Alfa AF: 0.382 Hom.: 4954

Bravo AF: 0.414

Asia WGS AF: 0.579 AC: 2013 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.5
DANN	Benign	0.60
PhyloP100		-0.37
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: rs750686; hg19: chr6-152408126;