rs985192

Variant names:

• chr6-151962343-A-C
• rs985192
• NM_000125.4:c.1096+17835A>C

Your query was ambiguous. Multiple possible variants found:

• chr6-151962343-A-C
• chr6-151962343-A-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.1096+17835A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.759 in 151,952 control chromosomes in the GnomAD database, including 44,082 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 0.76 (44082 hom., cov: 30)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58
• Publications: 14 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.803 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.1096+17835A>C		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1102+17835A>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1096+17835A>C		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.1096+17835A>C		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.453-98648A>C		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.577+17835A>C		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.759 AC: 115217 AN: 151832 Hom.: 44076 Cov.: 30

Gnomad AFR AF: 0.697

Gnomad AMI AF: 0.870

Gnomad AMR AF: 0.793

Gnomad ASJ AF: 0.806

Gnomad EAS AF: 0.572

Gnomad SAS AF: 0.596

Gnomad FIN AF: 0.758

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.809

Gnomad OTH AF: 0.787

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

GnomAD4 genome AF: 0.759 AC: 115266 AN: 151952 Hom.: 44082 Cov.: 30 AF XY: 0.754 AC XY: 56001 AN XY: 74268

African (AFR) AF: 0.697 AC: 28863 AN: 41414

American (AMR) AF: 0.793 AC: 12110 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.806 AC: 2794 AN: 3468

East Asian (EAS) AF: 0.571 AC: 2941 AN: 5148

South Asian (SAS) AF: 0.597 AC: 2868 AN: 4808

European-Finnish (FIN) AF: 0.758 AC: 8001 AN: 10554

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.809 AC: 54992 AN: 67966

Other (OTH) AF: 0.782 AC: 1649 AN: 2110

Alfa AF: 0.787 Hom.: 26518

Bravo AF: 0.759

Asia WGS AF: 0.588 AC: 2049 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	0.44
DANN	Benign	0.41
PhyloP100		-1.6
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: rs985192; hg19: chr6-152283478;