chr6-152099062-C-T

Variant names:

• chr6-152099062-C-T
• rs9341070
• NM_000125.4:c.*96C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000125.4(ESR1):​c.*96C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 930,322 control chromosomes in the GnomAD database, including 7 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 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (6 hom.)
• Consequence: ESR1 NM_000125.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.451
• Publications: 18 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.*96C>T		3_prime_UTR	Exon 8 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.*96C>T		3_prime_UTR	Exon 9 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.*96C>T		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.*96C>T		3_prime_UTR	Exon 8 of 8	ENSP00000206249.3
	ESR1	ENST00000427531.6	TSL:1	c.851-26204C>T		intron	N/A	ENSP00000394721.2
	ESR1	ENST00000440973.5	TSL:5	c.*96C>T		3_prime_UTR	Exon 10 of 10	ENSP00000405330.1

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00278

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00212 AC: 1646 AN: 778032 Hom.: 6 Cov.: 10 AF XY: 0.00213 AC XY: 860 AN XY: 404640

African (AFR) AF: 0.000493 AC: 10 AN: 20288

American (AMR) AF: 0.00165 AC: 58 AN: 35228

Ashkenazi Jewish (ASJ) AF: 0.00146 AC: 31 AN: 21190

East Asian (EAS) AF: 0.000209 AC: 7 AN: 33468

South Asian (SAS) AF: 0.000629 AC: 42 AN: 66754

European-Finnish (FIN) AF: 0.00131 AC: 52 AN: 39686

Middle Eastern (MID) AF: 0.0101 AC: 41 AN: 4076

European-Non Finnish (NFE) AF: 0.00250 AC: 1300 AN: 519472

Other (OTH) AF: 0.00277 AC: 105 AN: 37870

GnomAD4 genome AF: 0.00175 AC: 266 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74460

African (AFR) AF: 0.000481 AC: 20 AN: 41562

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.00278 AC: 189 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00221 Hom.: 0

Bravo AF: 0.00178

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	11
DANN	Benign	0.70
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism

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: rs9341070; hg19: chr6-152420197;