6-151986571-T-C

Variant names:

• chr6-151986571-T-C
• rs2144025
• NM_000125.4:c.1097-25085T>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.1097-25085T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.756 in 152,036 control chromosomes in the GnomAD database, including 44,957 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 0.76 (44957 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.919
• Publications: 32 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-25085T>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.1097-25085T>C		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114804 AN: 151920 Hom.: 44932 Cov.: 33

Gnomad AFR AF: 0.577

Gnomad AMI AF: 0.879

Gnomad AMR AF: 0.843

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.457

Gnomad SAS AF: 0.719

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.772

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

GnomAD4 genome AF: 0.756 AC: 114873 AN: 152036 Hom.: 44957 Cov.: 33 AF XY: 0.751 AC XY: 55793 AN XY: 74300

African (AFR) AF: 0.577 AC: 23882 AN: 41386

American (AMR) AF: 0.843 AC: 12892 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3154 AN: 3472

East Asian (EAS) AF: 0.458 AC: 2363 AN: 5162

South Asian (SAS) AF: 0.720 AC: 3470 AN: 4818

European-Finnish (FIN) AF: 0.749 AC: 7929 AN: 10586

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.860 AC: 58504 AN: 68000

Other (OTH) AF: 0.768 AC: 1621 AN: 2112

Alfa AF: 0.836 Hom.: 112923

Bravo AF: 0.753

Asia WGS AF: 0.596 AC: 2077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.23
DANN	Benign	0.56
PhyloP100		-0.92
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: rs2144025; hg19: chr6-152307706;