rs2179922

Variant names:

• chr6-151975965-A-G
• rs2179922
• NM_000125.4:c.1096+31457A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-151975965-A-G
• chr6-151975965-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000125.4(ESR1):​c.1096+31457A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.896 in 152,138 control chromosomes in the GnomAD database, including 61,295 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 0.90 (61295 hom., cov: 30)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.51
• Publications: 11 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 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.1096+31457A>G		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1102+31457A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1096+31457A>G		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.1096+31457A>G		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.453-85026A>G		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.577+31457A>G		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.896 AC: 136182 AN: 152020 Hom.: 61262 Cov.: 30

Gnomad AFR AF: 0.929

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.916

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.904

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

GnomAD4 genome AF: 0.896 AC: 136272 AN: 152138 Hom.: 61295 Cov.: 30 AF XY: 0.890 AC XY: 66201 AN XY: 74356

African (AFR) AF: 0.929 AC: 38564 AN: 41530

American (AMR) AF: 0.915 AC: 13991 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.931 AC: 3232 AN: 3472

East Asian (EAS) AF: 0.674 AC: 3460 AN: 5132

South Asian (SAS) AF: 0.770 AC: 3710 AN: 4818

European-Finnish (FIN) AF: 0.826 AC: 8749 AN: 10594

Middle Eastern (MID) AF: 0.946 AC: 278 AN: 294

European-Non Finnish (NFE) AF: 0.905 AC: 61560 AN: 67992

Other (OTH) AF: 0.900 AC: 1899 AN: 2110

Alfa AF: 0.899 Hom.: 79399

Bravo AF: 0.904

Asia WGS AF: 0.725 AC: 2524 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.058
DANN	Benign	0.80
PhyloP100		-2.5
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: rs2179922; hg19: chr6-152297100;