NM_000125.4:c.1096+5029C>T

Variant names:

• chr6-151949537-C-T
• rs3020314
• NM_000125.4:c.1096+5029C>T

Variant summary

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

The NM_000125.4(ESR1):​c.1096+5029C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 152,148 control chromosomes in the GnomAD database, including 23,484 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 0.53 (23484 hom., cov: 33)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 85 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.67 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.1096+5029C>T		intron	N/A	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.1102+5029C>T		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1096+5029C>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.1096+5029C>T		intron	N/A	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.453-111454C>T		intron	N/A	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000427531.6	TSL:1	c.577+5029C>T		intron	N/A	ENSP00000394721.2	P03372-4

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79970 AN: 152030 Hom.: 23488 Cov.: 33

Gnomad AFR AF: 0.292

Gnomad AMI AF: 0.713

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.661

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.405

Gnomad FIN AF: 0.656

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.568

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

GnomAD4 genome AF: 0.526 AC: 79979 AN: 152148 Hom.: 23484 Cov.: 33 AF XY: 0.521 AC XY: 38758 AN XY: 74374

African (AFR) AF: 0.292 AC: 12125 AN: 41506

American (AMR) AF: 0.503 AC: 7691 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 2294 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1034 AN: 5178

South Asian (SAS) AF: 0.407 AC: 1961 AN: 4818

European-Finnish (FIN) AF: 0.656 AC: 6947 AN: 10592

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45884 AN: 67980

Other (OTH) AF: 0.563 AC: 1186 AN: 2108

Alfa AF: 0.617 Hom.: 99477

Bravo AF: 0.500

Asia WGS AF: 0.309 AC: 1077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.79
DANN	Benign	0.59
PhyloP100		-0.27
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3020314; hg19: chr6-152270672;