6-152097440-T-C

Variant names:

• chr6-152097440-T-C
• rs3778099
• NM_000125.4:c.1554-1292T>C

Variant summary

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

The NM_000125.4(ESR1):​c.1554-1292T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 151,910 control chromosomes in the GnomAD database, including 1,937 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 0.14 (1937 hom., cov: 31)
• Consequence: ESR1 NM_000125.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.250
• Publications: 30 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1554-1292T>C		intron_variant	Intron 7 of 7	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1554-1292T>C		intron_variant	Intron 7 of 7	1	NM_000125.4	ENSP00000206249.3

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21796 AN: 151792 Hom.: 1931 Cov.: 31

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0775

Gnomad ASJ AF: 0.115

Gnomad EAS AF: 0.384

Gnomad SAS AF: 0.180

Gnomad FIN AF: 0.221

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.133

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

GnomAD4 genome AF: 0.144 AC: 21817 AN: 151910 Hom.: 1937 Cov.: 31 AF XY: 0.148 AC XY: 11011 AN XY: 74232

African (AFR) AF: 0.188 AC: 7780 AN: 41394

American (AMR) AF: 0.0773 AC: 1181 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 399 AN: 3464

East Asian (EAS) AF: 0.384 AC: 1981 AN: 5156

South Asian (SAS) AF: 0.178 AC: 857 AN: 4806

European-Finnish (FIN) AF: 0.221 AC: 2322 AN: 10524

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6906 AN: 67974

Other (OTH) AF: 0.134 AC: 282 AN: 2110

Alfa AF: 0.109 Hom.: 2082

Bravo AF: 0.134

Asia WGS AF: 0.278 AC: 963 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.25
DANN	Benign	0.42
PhyloP100		-0.25
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: rs3778099; hg19: chr6-152418575;