6-151871196-G-C

Variant names:

• chr6-151871196-G-C
• rs2431260
• NM_000125.4:c.644-9459G>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.644-9459G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.761 in 151,642 control chromosomes in the GnomAD database, including 44,839 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 (44839 hom., cov: 29)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.35
• Publications: 8 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=-1.05).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.892 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.644-9459G>C		intron_variant	Intron 2 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.644-9459G>C		intron_variant	Intron 2 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115248 AN: 151526 Hom.: 44807 Cov.: 29

Gnomad AFR AF: 0.900

Gnomad AMI AF: 0.793

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.829

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.633

Gnomad FIN AF: 0.726

Gnomad MID AF: 0.809

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.765

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

GnomAD4 genome AF: 0.761 AC: 115329 AN: 151642 Hom.: 44839 Cov.: 29 AF XY: 0.754 AC XY: 55836 AN XY: 74080

African (AFR) AF: 0.899 AC: 37249 AN: 41414

American (AMR) AF: 0.606 AC: 9217 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.829 AC: 2878 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2472 AN: 5136

South Asian (SAS) AF: 0.633 AC: 3030 AN: 4788

European-Finnish (FIN) AF: 0.726 AC: 7562 AN: 10416

Middle Eastern (MID) AF: 0.825 AC: 241 AN: 292

European-Non Finnish (NFE) AF: 0.742 AC: 50355 AN: 67906

Other (OTH) AF: 0.762 AC: 1602 AN: 2102

Alfa AF: 0.671 Hom.: 1919

Bravo AF: 0.758

Asia WGS AF: 0.605 AC: 2105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.31
DANN	Benign	0.17
PhyloP100		-1.3
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: rs2431260; hg19: chr6-152192331;