rs1709183

Variant names:

• chr6-151872861-C-T
• rs1709183
• NM_000125.4:c.644-7794C>T

Variant summary

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

The NM_000125.4(ESR1):​c.644-7794C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.67 in 151,980 control chromosomes in the GnomAD database, including 34,731 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 0.67 (34731 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.888
• Publications: 35 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.722 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000125.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.644-7794C>T		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.650-7794C>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.644-7794C>T		intron	N/A	NP_001116212.1	P03372-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.644-7794C>T		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.452+64497C>T		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.125-7794C>T		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101836 AN: 151862 Hom.: 34721 Cov.: 32

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.821

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.620

Gnomad FIN AF: 0.710

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.727

Gnomad OTH AF: 0.690

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

GnomAD4 genome AF: 0.670 AC: 101881 AN: 151980 Hom.: 34731 Cov.: 32 AF XY: 0.665 AC XY: 49441 AN XY: 74298

African (AFR) AF: 0.627 AC: 25962 AN: 41428

American (AMR) AF: 0.554 AC: 8441 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 2848 AN: 3468

East Asian (EAS) AF: 0.449 AC: 2311 AN: 5152

South Asian (SAS) AF: 0.619 AC: 2979 AN: 4816

European-Finnish (FIN) AF: 0.710 AC: 7502 AN: 10572

Middle Eastern (MID) AF: 0.813 AC: 239 AN: 294

European-Non Finnish (NFE) AF: 0.727 AC: 49433 AN: 67978

Other (OTH) AF: 0.686 AC: 1448 AN: 2112

Alfa AF: 0.704 Hom.: 95425

Bravo AF: 0.657

Asia WGS AF: 0.572 AC: 1992 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.33
DANN	Benign	0.51
PhyloP100		-0.89
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: rs1709183; hg19: chr6-152193996;