6-152102770-T-A

Variant names:

• chr6-152102770-T-A
• rs1062577
• NM_000125.4:c.*3804T>A

Variant summary

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

The ENST00000206249.8(ESR1):​c.*3804T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.101 in 216,682 control chromosomes in the GnomAD database, including 1,473 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 0.094 (823 hom., cov: 32)
  • Exomes 𝑓: 0.12 (650 hom.)
• Consequence: ESR1 ENST00000206249.8 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.782
• Publications: 35 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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.249 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000206249.8. 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.*3804T>A		3_prime_UTR	Exon 8 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.*3804T>A		3_prime_UTR	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.*3804T>A		3_prime_UTR	Exon 9 of 9	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.*3804T>A		3_prime_UTR	Exon 8 of 8	ENSP00000206249.3
	ESR1	ENST00000427531.6	TSL:1	c.851-22496T>A		intron	N/A	ENSP00000394721.2
	ESR1	ENST00000440973.5	TSL:5	c.*3804T>A		3_prime_UTR	Exon 10 of 10	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.0939 AC: 14267 AN: 151988 Hom.: 819 Cov.: 32

Gnomad AFR AF: 0.0892

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.0818

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.0776

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0695

Gnomad OTH AF: 0.121

GnomAD4 exome AF: 0.117 AC: 7528 AN: 64574 Hom.: 650 Cov.: 0 AF XY: 0.118 AC XY: 3529 AN XY: 30024

African (AFR) AF: 0.0866 AC: 253 AN: 2920

American (AMR) AF: 0.163 AC: 313 AN: 1918

Ashkenazi Jewish (ASJ) AF: 0.0849 AC: 342 AN: 4030

East Asian (EAS) AF: 0.294 AC: 2821 AN: 9580

South Asian (SAS) AF: 0.113 AC: 62 AN: 548

European-Finnish (FIN) AF: 0.0714 AC: 33 AN: 462

Middle Eastern (MID) AF: 0.105 AC: 42 AN: 400

European-Non Finnish (NFE) AF: 0.0795 AC: 3127 AN: 39330

Other (OTH) AF: 0.0993 AC: 535 AN: 5386

GnomAD4 genome AF: 0.0940 AC: 14295 AN: 152108 Hom.: 823 Cov.: 32 AF XY: 0.0965 AC XY: 7179 AN XY: 74372

African (AFR) AF: 0.0897 AC: 3722 AN: 41496

American (AMR) AF: 0.148 AC: 2259 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0818 AC: 284 AN: 3472

East Asian (EAS) AF: 0.261 AC: 1351 AN: 5176

South Asian (SAS) AF: 0.157 AC: 756 AN: 4816

European-Finnish (FIN) AF: 0.0776 AC: 823 AN: 10602

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0695 AC: 4726 AN: 67984

Other (OTH) AF: 0.120 AC: 252 AN: 2098

Alfa AF: 0.0243 Hom.: 20

Bravo AF: 0.0978

Asia WGS AF: 0.176 AC: 614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.6
DANN	Benign	0.83
PhyloP100		0.78
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: rs1062577; hg19: chr6-152423905; COSMIC: COSV52802680; COSMIC: COSV52802680;