rs9340799

Variant names:

• chr6-151842246-A-G
• rs9340799
• NM_000125.4:c.453-351A>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.453-351A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 151,976 control chromosomes in the GnomAD database, including 7,698 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 0.31 (7698 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.373

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.453-351A>G		intron_variant	Intron 1 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.453-351A>G		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47759 AN: 151858 Hom.: 7690 Cov.: 32

Gnomad AFR AF: 0.286

Gnomad AMI AF: 0.319

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.369

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.324

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

GnomAD4 genome AF: 0.315 AC: 47801 AN: 151976 Hom.: 7698 Cov.: 32 AF XY: 0.308 AC XY: 22896 AN XY: 74288

African (AFR) AF: 0.286 AC: 11864 AN: 41440

American (AMR) AF: 0.287 AC: 4388 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1339 AN: 3466

East Asian (EAS) AF: 0.201 AC: 1037 AN: 5156

South Asian (SAS) AF: 0.368 AC: 1773 AN: 4822

European-Finnish (FIN) AF: 0.233 AC: 2462 AN: 10554

Middle Eastern (MID) AF: 0.408 AC: 120 AN: 294

European-Non Finnish (NFE) AF: 0.351 AC: 23845 AN: 67946

Other (OTH) AF: 0.323 AC: 683 AN: 2112

Alfa AF: 0.336 Hom.: 17206

Bravo AF: 0.313

Asia WGS AF: 0.276 AC: 960 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.69
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

Publications

LitVar

Other links and lift over

dbSNP: rs9340799; hg19: chr6-152163381;