NM_000125.4:c.1097-31146A>G

Variant names:

• chr6-151980510-A-G
• rs3020327
• NM_000125.4:c.1097-31146A>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.1097-31146A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.894 in 152,194 control chromosomes in the GnomAD database, including 61,043 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 0.89 (61043 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48
• 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: 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=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.915 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1097-31146A>G		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1103-31146A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1097-31146A>G		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1097-31146A>G		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-80481A>G		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.578-31146A>G		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.894 AC: 135927 AN: 152076 Hom.: 61011 Cov.: 31

Gnomad AFR AF: 0.923

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.915

Gnomad ASJ AF: 0.931

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.770

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.905

Gnomad OTH AF: 0.902

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

GnomAD4 genome AF: 0.894 AC: 136016 AN: 152194 Hom.: 61043 Cov.: 31 AF XY: 0.888 AC XY: 66072 AN XY: 74380

African (AFR) AF: 0.923 AC: 38334 AN: 41552

American (AMR) AF: 0.915 AC: 13994 AN: 15294

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

East Asian (EAS) AF: 0.669 AC: 3449 AN: 5158

South Asian (SAS) AF: 0.770 AC: 3704 AN: 4810

European-Finnish (FIN) AF: 0.826 AC: 8730 AN: 10566

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

European-Non Finnish (NFE) AF: 0.905 AC: 61568 AN: 68022

Other (OTH) AF: 0.898 AC: 1898 AN: 2114

Alfa AF: 0.909 Hom.: 11839

Bravo AF: 0.901

Asia WGS AF: 0.722 AC: 2515 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.28
DANN	Benign	0.33
PhyloP100		-1.5
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: rs3020327; hg19: chr6-152301645;