rs6903180

Variant names:

• chr6-151804096-G-A
• rs6903180
• ENST00000404742.5:c.-70-3747G>A

Variant summary

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

The ENST00000404742.5(ESR1):​c.-70-3747G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.28 (765 hom., cov: 0)
• Consequence: ESR1 ENST00000404742.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.863
• 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_001122742.2	c.-70-3747G>A		intron_variant	Intron 2 of 9		NP_001116214.1
ESR1	NM_001385568.1	c.-70-3747G>A		intron_variant	Intron 2 of 9		NP_001372497.1
ESR1	NM_001385570.1	c.-70-3747G>A		intron_variant	Intron 2 of 8		NP_001372499.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000404742.5	c.-70-3747G>A		intron_variant	Intron 2 of 2	1		ENSP00000385373.1
ESR1	ENST00000473497.5	n.205-3747G>A		intron_variant	Intron 2 of 2	1
ESR1	ENST00000440973.5	c.-70-3747G>A		intron_variant	Intron 2 of 9	5		ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.275 AC: 11837 AN: 43036 Hom.: 756 Cov.: 0

Gnomad AFR AF: 0.459

Gnomad AMI AF: 0.00556

Gnomad AMR AF: 0.231

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.125

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.254

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

GnomAD4 genome AF: 0.275 AC: 11869 AN: 43086 Hom.: 765 Cov.: 0 AF XY: 0.274 AC XY: 5938 AN XY: 21646

African (AFR) AF: 0.459 AC: 7173 AN: 15636

American (AMR) AF: 0.231 AC: 823 AN: 3558

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 232 AN: 954

East Asian (EAS) AF: 0.291 AC: 739 AN: 2540

South Asian (SAS) AF: 0.348 AC: 755 AN: 2170

European-Finnish (FIN) AF: 0.0865 AC: 250 AN: 2890

Middle Eastern (MID) AF: 0.120 AC: 6 AN: 50

European-Non Finnish (NFE) AF: 0.119 AC: 1728 AN: 14502

Other (OTH) AF: 0.267 AC: 162 AN: 606

Alfa AF: 0.0468 Hom.: 449

Bravo AF: 0.0802

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.55
PhyloP100		-0.86
PromoterAI		-0.0053	Neutral
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: rs6903180; hg19: chr6-152125231;