rs3778079

Variant names:

• chr6-152063094-A-G
• rs3778079
• NM_000125.4:c.1369+1970A>G

Variant summary

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

The NM_000125.4(ESR1):​c.1369+1970A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 152,018 control chromosomes in the GnomAD database, including 5,618 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 0.22 (5618 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.850
• Publications: 4 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.448 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1369+1970A>G		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1375+1970A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1369+1970A>G		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1369+1970A>G		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.586+1970A>G		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.850+1970A>G		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.224 AC: 33954 AN: 151900 Hom.: 5608 Cov.: 32

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.130

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.200

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.224 AC: 34003 AN: 152018 Hom.: 5618 Cov.: 32 AF XY: 0.224 AC XY: 16667 AN XY: 74306

African (AFR) AF: 0.453 AC: 18775 AN: 41446

American (AMR) AF: 0.107 AC: 1643 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 383 AN: 3472

East Asian (EAS) AF: 0.369 AC: 1899 AN: 5146

South Asian (SAS) AF: 0.228 AC: 1098 AN: 4820

European-Finnish (FIN) AF: 0.200 AC: 2110 AN: 10574

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7507 AN: 67964

Other (OTH) AF: 0.207 AC: 436 AN: 2106

Alfa AF: 0.178 Hom.: 537

Bravo AF: 0.225

Asia WGS AF: 0.297 AC: 1030 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.59
DANN	Benign	0.58
PhyloP100		-0.85
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: rs3778079; hg19: chr6-152384229;