NM_000125.4:c.761-3195A>G

Variant names:

• chr6-151940978-A-G
• rs9371564
• NM_000125.4:c.761-3195A>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.761-3195A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.548 in 152,064 control chromosomes in the GnomAD database, including 24,459 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 0.55 (24459 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.103

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.663 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.761-3195A>G		intron_variant	Intron 3 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.761-3195A>G		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83242 AN: 151946 Hom.: 24465 Cov.: 33

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.766

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.720

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.668

Gnomad OTH AF: 0.577

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

GnomAD4 genome AF: 0.548 AC: 83263 AN: 152064 Hom.: 24459 Cov.: 33 AF XY: 0.543 AC XY: 40354 AN XY: 74322

African (AFR) AF: 0.360 AC: 14922 AN: 41464

American (AMR) AF: 0.509 AC: 7771 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 2498 AN: 3468

East Asian (EAS) AF: 0.291 AC: 1503 AN: 5166

South Asian (SAS) AF: 0.407 AC: 1961 AN: 4822

European-Finnish (FIN) AF: 0.669 AC: 7077 AN: 10574

Middle Eastern (MID) AF: 0.728 AC: 214 AN: 294

European-Non Finnish (NFE) AF: 0.668 AC: 45410 AN: 67974

Other (OTH) AF: 0.572 AC: 1210 AN: 2116

Alfa AF: 0.611 Hom.: 15242

Bravo AF: 0.524

Asia WGS AF: 0.353 AC: 1232 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.53
PhyloP100		0.10
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

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Other links and lift over

dbSNP: rs9371564; hg19: chr6-152262113;