rs9383938

Variant names:

• chr6-151666222-G-T
• rs9383938
• ENST00000473497.5:n.73+9459G>T

Variant summary

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

The ENST00000473497.5(ESR1):​n.73+9459G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 152,202 control chromosomes in the GnomAD database, including 1,136 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 0.11 (1136 hom., cov: 32)
• Consequence: ESR1 ENST00000473497.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.452
• Publications: 43 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESR1	XM_047418290.1	c.-428G>T		5_prime_UTR_variant	Exon 1 of 10		XP_047274246.1
ESR1	NM_001385568.1	c.-202+9459G>T		intron_variant	Intron 1 of 9		NP_001372497.1
ESR1	XM_017010377.2	c.-260-168G>T		intron_variant	Intron 1 of 10		XP_016865866.1
ESR1	XM_017010380.2	c.-71+9459G>T		intron_variant	Intron 1 of 8		XP_016865869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000473497.5	n.73+9459G>T		intron_variant	Intron 1 of 2	1

Frequencies

GnomAD3 genomes AF: 0.110 AC: 16708 AN: 152084 Hom.: 1136 Cov.: 32

Gnomad AFR AF: 0.153

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.355

Gnomad SAS AF: 0.0983

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0834

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.110 AC: 16707 AN: 152202 Hom.: 1136 Cov.: 32 AF XY: 0.108 AC XY: 8046 AN XY: 74418

African (AFR) AF: 0.153 AC: 6352 AN: 41498

American (AMR) AF: 0.0848 AC: 1296 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0911 AC: 316 AN: 3470

East Asian (EAS) AF: 0.355 AC: 1836 AN: 5168

South Asian (SAS) AF: 0.0977 AC: 472 AN: 4830

European-Finnish (FIN) AF: 0.0390 AC: 414 AN: 10608

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5668 AN: 68014

Other (OTH) AF: 0.122 AC: 258 AN: 2116

Alfa AF: 0.0950 Hom.: 1854

Bravo AF: 0.117

Asia WGS AF: 0.206 AC: 716 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.54
PhyloP100		0.45

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9383938; hg19: chr6-151987357;