6-151809179-C-T

Variant names:

• chr6-151809179-C-T
• rs9340774
• ENST00000427531.6:c.-160C>T

Variant summary

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

The ENST00000427531.6(ESR1):​c.-160C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0202 in 455,048 control chromosomes in the GnomAD database, including 692 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 0.047 (577 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (115 hom.)
• Consequence: ESR1 ENST00000427531.6 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0330
• Publications: 4 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 (REVEL=0.007).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.452+815C>T		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+815C>T		intron_variant	Intron 1 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7174 AN: 152182 Hom.: 571 Cov.: 33

Gnomad AFR AF: 0.163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.0330

GnomAD2 exomes AF: 0.00999 AC: 1449 AN: 145046 AF XY: 0.00847

Gnomad AFR exome AF: 0.166

Gnomad AMR exome AF: 0.00739

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00126

Gnomad NFE exome AF: 0.000728

Gnomad OTH exome AF: 0.00652

GnomAD4 exome AF: 0.00649 AC: 1964 AN: 302748 Hom.: 115 Cov.: 0 AF XY: 0.00524 AC XY: 885 AN XY: 169038

African (AFR) AF: 0.160 AC: 1315 AN: 8232

American (AMR) AF: 0.00740 AC: 197 AN: 26632

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 112 AN: 10630

East Asian (EAS) AF: 0.00 AC: 0 AN: 8316

South Asian (SAS) AF: 0.000479 AC: 28 AN: 58404

European-Finnish (FIN) AF: 0.00123 AC: 33 AN: 26918

Middle Eastern (MID) AF: 0.00989 AC: 27 AN: 2730

European-Non Finnish (NFE) AF: 0.000584 AC: 86 AN: 147330

Other (OTH) AF: 0.0122 AC: 166 AN: 13556

GnomAD4 genome AF: 0.0473 AC: 7207 AN: 152300 Hom.: 577 Cov.: 33 AF XY: 0.0453 AC XY: 3372 AN XY: 74492

African (AFR) AF: 0.163 AC: 6778 AN: 41538

American (AMR) AF: 0.0174 AC: 267 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68020

Other (OTH) AF: 0.0326 AC: 69 AN: 2116

Alfa AF: 0.0484 Hom.: 297

Bravo AF: 0.0548

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.0
DANN	Benign	0.73
PhyloP100		0.033
PromoterAI		0.020	Neutral
Mutation Taster		=300/0	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: rs9340774; hg19: chr6-152130314; COSMIC: COSV52787597;