NM_000125.4:c.761-30408A>G

Variant names:

• chr6-151913765-A-G
• rs12199722
• NM_000125.4:c.761-30408A>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.761-30408A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,100 control chromosomes in the GnomAD database, including 4,564 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 0.22 (4564 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 9 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.761-30408A>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.761-30408A>G		intron_variant	Intron 3 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33374 AN: 151984 Hom.: 4565 Cov.: 32

Gnomad AFR AF: 0.0599

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.0381

Gnomad SAS AF: 0.251

Gnomad FIN AF: 0.249

Gnomad MID AF: 0.348

Gnomad NFE AF: 0.309

Gnomad OTH AF: 0.241

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

GnomAD4 genome AF: 0.219 AC: 33378 AN: 152100 Hom.: 4564 Cov.: 32 AF XY: 0.217 AC XY: 16107 AN XY: 74334

African (AFR) AF: 0.0597 AC: 2478 AN: 41528

American (AMR) AF: 0.241 AC: 3678 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1241 AN: 3468

East Asian (EAS) AF: 0.0380 AC: 197 AN: 5184

South Asian (SAS) AF: 0.252 AC: 1215 AN: 4822

European-Finnish (FIN) AF: 0.249 AC: 2630 AN: 10570

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.309 AC: 20993 AN: 67964

Other (OTH) AF: 0.240 AC: 507 AN: 2110

Alfa AF: 0.265 Hom.: 764

Bravo AF: 0.211

Asia WGS AF: 0.148 AC: 515 AN: 3452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.69
DANN	Benign	0.54
PhyloP100		0.18
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: rs12199722; hg19: chr6-152234900; COSMIC: COSV52785436;