rs3844508

Variant names:

• chr6-151818907-A-G
• rs3844508
• NM_000125.4:c.452+10543A>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.452+10543A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,008 control chromosomes in the GnomAD database, including 4,926 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 (4926 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.72
• Publications: 16 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 = 0.403 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.452+10543A>G		intron_variant	Intron 1 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.452+10543A>G		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34418 AN: 151890 Hom.: 4911 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.292

Gnomad SAS AF: 0.221

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.205

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

GnomAD4 genome AF: 0.227 AC: 34474 AN: 152008 Hom.: 4926 Cov.: 32 AF XY: 0.229 AC XY: 17028 AN XY: 74316

African (AFR) AF: 0.408 AC: 16902 AN: 41388

American (AMR) AF: 0.238 AC: 3640 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 515 AN: 3466

East Asian (EAS) AF: 0.292 AC: 1506 AN: 5162

South Asian (SAS) AF: 0.220 AC: 1057 AN: 4806

European-Finnish (FIN) AF: 0.162 AC: 1717 AN: 10596

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.126 AC: 8541 AN: 68000

Other (OTH) AF: 0.213 AC: 450 AN: 2112

Alfa AF: 0.193 Hom.: 580

Bravo AF: 0.238

Asia WGS AF: 0.293 AC: 1015 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.084
DANN	Benign	0.50
PhyloP100		-2.7
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: rs3844508; hg19: chr6-152140042;