chr6-152091002-T-C

Variant names:

• chr6-152091002-T-C
• rs3020382
• NM_000125.4:c.1370-3383T>C

Variant summary

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

The NM_000125.4(ESR1):​c.1370-3383T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 152,124 control chromosomes in the GnomAD database, including 1,670 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 0.14 (1670 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0410
• Publications: 12 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=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 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.1370-3383T>C		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1376-3383T>C		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1370-3383T>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.1370-3383T>C		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.587-3383T>C		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.850+29878T>C		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21957 AN: 152006 Hom.: 1665 Cov.: 32

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.215

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.215

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.143

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

GnomAD4 genome AF: 0.145 AC: 21984 AN: 152124 Hom.: 1670 Cov.: 32 AF XY: 0.144 AC XY: 10684 AN XY: 74346

African (AFR) AF: 0.117 AC: 4866 AN: 41488

American (AMR) AF: 0.119 AC: 1818 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 429 AN: 3470

East Asian (EAS) AF: 0.110 AC: 568 AN: 5174

South Asian (SAS) AF: 0.216 AC: 1038 AN: 4812

European-Finnish (FIN) AF: 0.137 AC: 1445 AN: 10582

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11276 AN: 67992

Other (OTH) AF: 0.143 AC: 301 AN: 2110

Alfa AF: 0.154 Hom.: 3393

Bravo AF: 0.139

Asia WGS AF: 0.151 AC: 526 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.2
DANN	Benign	0.74
PhyloP100		0.041
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: rs3020382; hg19: chr6-152412137; COSMIC: COSV52801297;