NM_000125.4:c.1097-16044T>C

Variant names:

• chr6-151995612-T-C
• rs17081994
• NM_000125.4:c.1097-16044T>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.1097-16044T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,234 control chromosomes in the GnomAD database, including 1,535 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 0.13 (1535 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.949
• Publications: 4 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 (EAS) allele frequency at 95% confidence interval = 0.318 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-16044T>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.1097-16044T>C		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19923 AN: 152116 Hom.: 1535 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.136

Gnomad AMR AF: 0.0766

Gnomad ASJ AF: 0.104

Gnomad EAS AF: 0.331

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.131 AC: 19944 AN: 152234 Hom.: 1535 Cov.: 32 AF XY: 0.135 AC XY: 10048 AN XY: 74422

African (AFR) AF: 0.144 AC: 5971 AN: 41542

American (AMR) AF: 0.0763 AC: 1168 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.104 AC: 360 AN: 3472

East Asian (EAS) AF: 0.331 AC: 1710 AN: 5168

South Asian (SAS) AF: 0.184 AC: 886 AN: 4826

European-Finnish (FIN) AF: 0.195 AC: 2067 AN: 10592

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7343 AN: 68016

Other (OTH) AF: 0.135 AC: 286 AN: 2114

Alfa AF: 0.130 Hom.: 464

Bravo AF: 0.122

Asia WGS AF: 0.251 AC: 870 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.1
DANN	Benign	0.72
PhyloP100		-0.95
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: rs17081994; hg19: chr6-152316747;