rs6905370

Variant names:

• chr6-152005062-G-A
• rs6905370
• NM_000125.4:c.1097-6594G>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.1097-6594G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 151,714 control chromosomes in the GnomAD database, including 12,929 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 0.38 (12929 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00400
• Publications: 13 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 (AFR) allele frequency at 95% confidence interval = 0.6 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1097-6594G>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.1097-6594G>A		intron_variant	Intron 4 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.383 AC: 58008 AN: 151596 Hom.: 12888 Cov.: 32

Gnomad AFR AF: 0.605

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.233

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.542

Gnomad SAS AF: 0.504

Gnomad FIN AF: 0.339

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.276

Gnomad OTH AF: 0.350

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

GnomAD4 genome AF: 0.383 AC: 58110 AN: 151714 Hom.: 12929 Cov.: 32 AF XY: 0.385 AC XY: 28565 AN XY: 74106

African (AFR) AF: 0.606 AC: 25101 AN: 41410

American (AMR) AF: 0.233 AC: 3541 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 832 AN: 3460

East Asian (EAS) AF: 0.541 AC: 2770 AN: 5118

South Asian (SAS) AF: 0.503 AC: 2419 AN: 4810

European-Finnish (FIN) AF: 0.339 AC: 3573 AN: 10532

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.276 AC: 18734 AN: 67856

Other (OTH) AF: 0.355 AC: 749 AN: 2112

Alfa AF: 0.349 Hom.: 1387

Bravo AF: 0.379

Asia WGS AF: 0.542 AC: 1884 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.1
DANN	Benign	0.76
PhyloP100		-0.0040
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6905370; hg19: chr6-152326197; COSMIC: COSV52800822;