6-151881969-A-G

Variant names:

• chr6-151881969-A-G
• rs6557170
• NM_000125.4:c.760+1198A>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.760+1198A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.786 in 151,912 control chromosomes in the GnomAD database, including 47,616 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 0.79 (47616 hom., cov: 30)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.632
• Publications: 22 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=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 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.760+1198A>G		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.766+1198A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.760+1198A>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.760+1198A>G		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+73605A>G		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.241+1198A>G		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.786 AC: 119322 AN: 151796 Hom.: 47577 Cov.: 30

Gnomad AFR AF: 0.904

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.732

Gnomad ASJ AF: 0.838

Gnomad EAS AF: 0.518

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.810

Gnomad NFE AF: 0.766

Gnomad OTH AF: 0.789

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

GnomAD4 genome AF: 0.786 AC: 119415 AN: 151912 Hom.: 47616 Cov.: 30 AF XY: 0.779 AC XY: 57781 AN XY: 74196

African (AFR) AF: 0.904 AC: 37451 AN: 41434

American (AMR) AF: 0.732 AC: 11184 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.838 AC: 2911 AN: 3472

East Asian (EAS) AF: 0.517 AC: 2663 AN: 5154

South Asian (SAS) AF: 0.624 AC: 2992 AN: 4796

European-Finnish (FIN) AF: 0.709 AC: 7436 AN: 10488

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.766 AC: 52099 AN: 67974

Other (OTH) AF: 0.786 AC: 1653 AN: 2104

Alfa AF: 0.773 Hom.: 195669

Bravo AF: 0.794

Asia WGS AF: 0.611 AC: 2126 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.59
DANN	Benign	0.27
PhyloP100		-0.63
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: rs6557170; hg19: chr6-152203104;