rs17847065

chr6-151808349-C-Achr6-151808349-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000125.4(ESR1):c.437C>A(p.Pro146Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00186 in 1,511,840 control chromosomes in the GnomAD database, including 52 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 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (46 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.90

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004661292).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00296 (443/149476) while in subpopulation EAS AF= 0.0278 (137/4922). AF 95% confidence interval is 0.024. There are 6 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.437C>A	p.Pro146Gln	missense_variant	1/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.437C>A	p.Pro146Gln	missense_variant	1/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 445 AN: 149400 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000425

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.000868

Gnomad EAS AF: 0.0281

Gnomad SAS AF: 0.00232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00387

GnomAD3 exomes AF: 0.00585 AC: 802 AN: 137080 Hom.: 11 AF XY: 0.00516 AC XY: 389 AN XY: 75326

Gnomad AFR exome AF: 0.000361

Gnomad AMR exome AF: 0.0195

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0250

Gnomad SAS exome AF: 0.00167

Gnomad FIN exome AF: 0.000114

Gnomad NFE exome AF: 0.000216

Gnomad OTH exome AF: 0.00552

GnomAD4 exome AF: 0.00174 AC: 2369 AN: 1362364 Hom.: 46 Cov.: 37 AF XY: 0.00175 AC XY: 1173 AN XY: 668842

Gnomad4 AFR exome AF: 0.000296

Gnomad4 AMR exome AF: 0.0187

Gnomad4 ASJ exome AF: 0.000273

Gnomad4 EAS exome AF: 0.0401

Gnomad4 SAS exome AF: 0.00177

Gnomad4 FIN exome AF: 0.0000499

Gnomad4 NFE exome AF: 0.0000544

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00296 AC: 443 AN: 149476 Hom.: 6 Cov.: 32 AF XY: 0.00352 AC XY: 257 AN XY: 73058

Gnomad4 AFR AF: 0.000424

Gnomad4 AMR AF: 0.0175

Gnomad4 ASJ AF: 0.000868

Gnomad4 EAS AF: 0.0278

Gnomad4 SAS AF: 0.00232

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00385

Alfa AF: 0.00108 Hom.: 2

Bravo AF: 0.00357

ExAC AF: 0.00351 AC: 395

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;T;T;T;T;T
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.0047	T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M;M;M;M;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.71	N;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.11	T;T;T;T;D;D
Sift4G	Benign	0.20	T;T;T;T;D;D
Polyphen		0.93	P;P;P;P;D;.
Vest4		0.30
MVP		0.53
MPC		1.1
ClinPred		0.044	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.37

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

Publications

LitVar

Other links and lift over

dbSNP: rs17847065; hg19: chr6-152129484; COSMIC: COSV105858278; COSMIC: COSV105858278;