NM_000125.4:c.1235+1016G>A

Variant names:

• chr6-152012810-G-A
• rs9340978
• NM_000125.4:c.1235+1016G>A

Variant summary

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

The NM_000125.4(ESR1):​c.1235+1016G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 152,210 control chromosomes in the GnomAD database, including 224 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 0.049 (224 hom., cov: 32)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0590
• Publications: 13 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=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0637 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	NM_000125.4	MANE Select	c.1235+1016G>A		intron	N/A	NP_000116.2
	ESR1	NM_001291230.2		c.1241+1016G>A		intron	N/A	NP_001278159.1
	ESR1	NM_001122740.2		c.1235+1016G>A		intron	N/A	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.1235+1016G>A		intron	N/A	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.453-48181G>A		intron	N/A	ENSP00000384064.1
	ESR1	ENST00000427531.6	TSL:1	c.716+1016G>A		intron	N/A	ENSP00000394721.2

Frequencies

GnomAD3 genomes AF: 0.0486 AC: 7399 AN: 152092 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0523

Gnomad ASJ AF: 0.0861

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0192

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0653

Gnomad OTH AF: 0.0636

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

GnomAD4 genome AF: 0.0486 AC: 7399 AN: 152210 Hom.: 224 Cov.: 32 AF XY: 0.0477 AC XY: 3548 AN XY: 74396

African (AFR) AF: 0.0230 AC: 956 AN: 41544

American (AMR) AF: 0.0523 AC: 799 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0861 AC: 299 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5176

South Asian (SAS) AF: 0.0190 AC: 92 AN: 4830

European-Finnish (FIN) AF: 0.0464 AC: 491 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0653 AC: 4439 AN: 68002

Other (OTH) AF: 0.0630 AC: 133 AN: 2112

Alfa AF: 0.0602 Hom.: 746

Bravo AF: 0.0483

Asia WGS AF: 0.0140 AC: 48 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.71
PhyloP100		-0.059
Mutation Taster		=99/1	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: rs9340978; hg19: chr6-152333945; COSMIC: COSV52800858;