NM_000125.4:c.1096+24127T>C

Variant names:

• chr6-151968635-T-C
• rs3020318
• NM_000125.4:c.1096+24127T>C

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+24127T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.512 in 151,992 control chromosomes in the GnomAD database, including 23,007 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 0.51 (23007 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.263
• Publications: 17 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.664 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1096+24127T>C		intron_variant	Intron 4 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1096+24127T>C		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.512 AC: 77758 AN: 151874 Hom.: 23015 Cov.: 31

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.683

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.309

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.645

Gnomad OTH AF: 0.558

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

GnomAD4 genome AF: 0.512 AC: 77769 AN: 151992 Hom.: 23007 Cov.: 31 AF XY: 0.514 AC XY: 38143 AN XY: 74272

African (AFR) AF: 0.213 AC: 8821 AN: 41482

American (AMR) AF: 0.674 AC: 10298 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2265 AN: 3468

East Asian (EAS) AF: 0.309 AC: 1598 AN: 5164

South Asian (SAS) AF: 0.413 AC: 1985 AN: 4804

European-Finnish (FIN) AF: 0.661 AC: 6980 AN: 10556

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.645 AC: 43827 AN: 67936

Other (OTH) AF: 0.553 AC: 1167 AN: 2112

Alfa AF: 0.599 Hom.: 29795

Bravo AF: 0.501

Asia WGS AF: 0.367 AC: 1280 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.3
DANN	Benign	0.42
PhyloP100		0.26
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3020318; hg19: chr6-152289770;