6-151981443-G-A

Variant names:

• chr6-151981443-G-A
• rs726281
• NM_000125.4:c.1097-30213G>A

Variant summary

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

The NM_000125.4(ESR1):​c.1097-30213G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.566 in 152,096 control chromosomes in the GnomAD database, including 28,417 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 0.57 (28417 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.272
• Publications: 41 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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-30213G>A		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.1097-30213G>A		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.566 AC: 86034 AN: 151978 Hom.: 28421 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.712

Gnomad AMR AF: 0.719

Gnomad ASJ AF: 0.773

Gnomad EAS AF: 0.321

Gnomad SAS AF: 0.487

Gnomad FIN AF: 0.722

Gnomad MID AF: 0.766

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.613

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

GnomAD4 genome AF: 0.566 AC: 86048 AN: 152096 Hom.: 28417 Cov.: 33 AF XY: 0.567 AC XY: 42181 AN XY: 74354

African (AFR) AF: 0.224 AC: 9303 AN: 41482

American (AMR) AF: 0.719 AC: 10991 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.773 AC: 2684 AN: 3470

East Asian (EAS) AF: 0.322 AC: 1661 AN: 5164

South Asian (SAS) AF: 0.488 AC: 2352 AN: 4816

European-Finnish (FIN) AF: 0.722 AC: 7640 AN: 10578

Middle Eastern (MID) AF: 0.769 AC: 226 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49263 AN: 67988

Other (OTH) AF: 0.607 AC: 1283 AN: 2114

Alfa AF: 0.673 Hom.: 150712

Bravo AF: 0.550

Asia WGS AF: 0.400 AC: 1395 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.42
DANN	Benign	0.62
PhyloP100		-0.27
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: rs726281; hg19: chr6-152302578;