6-151975851-A-G

Variant names:

• chr6-151975851-A-G
• rs3020404
• NM_000125.4:c.1096+31343A>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+31343A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.232 in 152,154 control chromosomes in the GnomAD database, including 5,042 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 0.23 (5042 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.885
• Publications: 10 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.343 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.1096+31343A>G		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1102+31343A>G		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1096+31343A>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.1096+31343A>G		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-85140A>G		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.577+31343A>G		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35221 AN: 152036 Hom.: 5037 Cov.: 32

Gnomad AFR AF: 0.0596

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.277

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.267

Gnomad FIN AF: 0.340

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.291

Gnomad OTH AF: 0.251

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

GnomAD4 genome AF: 0.232 AC: 35233 AN: 152154 Hom.: 5042 Cov.: 32 AF XY: 0.237 AC XY: 17637 AN XY: 74356

African (AFR) AF: 0.0595 AC: 2471 AN: 41554

American (AMR) AF: 0.351 AC: 5360 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 960 AN: 3468

East Asian (EAS) AF: 0.168 AC: 869 AN: 5174

South Asian (SAS) AF: 0.269 AC: 1293 AN: 4808

European-Finnish (FIN) AF: 0.340 AC: 3594 AN: 10566

Middle Eastern (MID) AF: 0.351 AC: 101 AN: 288

European-Non Finnish (NFE) AF: 0.291 AC: 19785 AN: 67996

Other (OTH) AF: 0.249 AC: 525 AN: 2112

Alfa AF: 0.182 Hom.: 1427

Bravo AF: 0.225

Asia WGS AF: 0.214 AC: 749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.32
DANN	Benign	0.54
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: rs3020404; hg19: chr6-152296986;