NM_000125.4:c.452+89C>T

Variant names:

• chr6-151808453-C-T
• rs6914438
• NM_000125.4:c.452+89C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000125.4(ESR1):​c.452+89C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 1,144,474 control chromosomes in the GnomAD database, including 4,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.13 (2502 hom., cov: 32)
  • Exomes 𝑓: 0.023 (2032 hom.)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.74
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-151808453-C-T is Benign according to our data. Variant chr6-151808453-C-T is described in ClinVar as Benign. ClinVar VariationId is 1258285.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.307 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.452+89C>T		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.452+89C>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.452+89C>T		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.452+89C>T		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.452+89C>T		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000456483.3	TSL:1	c.452+89C>T		intron	N/A	ENSP00000415934.3	Q9H2M2

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19532 AN: 150968 Hom.: 2487 Cov.: 32

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.176

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.0478

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0231 AC: 22985 AN: 993400 Hom.: 2032 AF XY: 0.0244 AC XY: 11774 AN XY: 482950

African (AFR) AF: 0.241 AC: 3727 AN: 15458

American (AMR) AF: 0.142 AC: 1299 AN: 9128

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 602 AN: 14704

East Asian (EAS) AF: 0.236 AC: 5002 AN: 21226

South Asian (SAS) AF: 0.108 AC: 4262 AN: 39468

European-Finnish (FIN) AF: 0.00730 AC: 205 AN: 28082

Middle Eastern (MID) AF: 0.0460 AC: 132 AN: 2870

European-Non Finnish (NFE) AF: 0.00714 AC: 5865 AN: 821504

Other (OTH) AF: 0.0462 AC: 1891 AN: 40960

GnomAD4 genome AF: 0.130 AC: 19579 AN: 151074 Hom.: 2502 Cov.: 32 AF XY: 0.133 AC XY: 9802 AN XY: 73840

African (AFR) AF: 0.312 AC: 12714 AN: 40810

American (AMR) AF: 0.193 AC: 2934 AN: 15212

Ashkenazi Jewish (ASJ) AF: 0.0686 AC: 238 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1377 AN: 4980

South Asian (SAS) AF: 0.175 AC: 836 AN: 4778

European-Finnish (FIN) AF: 0.0119 AC: 126 AN: 10582

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0155 AC: 1055 AN: 67938

Other (OTH) AF: 0.136 AC: 285 AN: 2100

Alfa AF: 0.0699 Hom.: 154

Bravo AF: 0.154

Asia WGS AF: 0.255 AC: 881 AN: 3460

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	6.9
DANN	Benign	0.89
PhyloP100		-1.7
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: rs6914438; hg19: chr6-152129588;