chr6-151843104-C-T

Variant names:

• chr6-151843104-C-T
• rs7774230
• NM_000125.4:c.643+317C>T

Variant summary

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

The NM_001291230.2(ESR1):​c.649+311C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.464 in 151,990 control chromosomes in the GnomAD database, including 16,668 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 0.46 (16668 hom., cov: 32)
• Consequence: ESR1 NM_001291230.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.615
• Publications: 11 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 (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291230.2. 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.643+317C>T		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.649+311C>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.643+317C>T		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.643+317C>T		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.452+34740C>T		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.124+317C>T		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70403 AN: 151872 Hom.: 16652 Cov.: 32

Gnomad AFR AF: 0.532

Gnomad AMI AF: 0.509

Gnomad AMR AF: 0.364

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.398

Gnomad SAS AF: 0.432

Gnomad FIN AF: 0.398

Gnomad MID AF: 0.436

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.441

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

GnomAD4 genome AF: 0.464 AC: 70465 AN: 151990 Hom.: 16668 Cov.: 32 AF XY: 0.457 AC XY: 33940 AN XY: 74278

African (AFR) AF: 0.533 AC: 22078 AN: 41454

American (AMR) AF: 0.364 AC: 5552 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.457 AC: 1586 AN: 3472

East Asian (EAS) AF: 0.397 AC: 2046 AN: 5152

South Asian (SAS) AF: 0.430 AC: 2070 AN: 4810

European-Finnish (FIN) AF: 0.398 AC: 4204 AN: 10572

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.462 AC: 31403 AN: 67952

Other (OTH) AF: 0.444 AC: 938 AN: 2114

Alfa AF: 0.474 Hom.: 2214

Bravo AF: 0.460

Asia WGS AF: 0.421 AC: 1459 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.046
DANN	Benign	0.23
PhyloP100		-0.61
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: rs7774230; hg19: chr6-152164239;