rs9371562

Variant names:

• chr6-151939507-T-A
• rs9371562
• NM_000125.4:c.761-4666T>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.761-4666T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 152,290 control chromosomes in the GnomAD database, including 108 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 0.025 (108 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 5 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0696 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.761-4666T>A		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.767-4666T>A		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.761-4666T>A		intron	N/A	NP_001116212.1	P03372-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.761-4666T>A		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.453-121484T>A		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.242-4666T>A		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.0252 AC: 3830 AN: 152172 Hom.: 106 Cov.: 32

Gnomad AFR AF: 0.0664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.0753

Gnomad SAS AF: 0.0236

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.0143

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

GnomAD4 genome AF: 0.0252 AC: 3840 AN: 152290 Hom.: 108 Cov.: 32 AF XY: 0.0265 AC XY: 1971 AN XY: 74474

African (AFR) AF: 0.0664 AC: 2758 AN: 41550

American (AMR) AF: 0.00647 AC: 99 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.0758 AC: 393 AN: 5184

South Asian (SAS) AF: 0.0236 AC: 114 AN: 4832

European-Finnish (FIN) AF: 0.0269 AC: 285 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00204 AC: 139 AN: 68022

Other (OTH) AF: 0.0147 AC: 31 AN: 2114

Alfa AF: 0.0160 Hom.: 7

Bravo AF: 0.0251

Asia WGS AF: 0.0450 AC: 155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.28
DANN	Benign	0.54
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs9371562; hg19: chr6-152260642;