rs17847065

Variant names:

• chr6-151808349-C-A
• rs17847065
• NM_000125.4:c.437C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-151808349-C-A
• chr6-151808349-C-G
• chr6-151808349-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0030 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (46 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.90
• 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: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004661292).
• BP6: Variant 6-151808349-C-A is Benign according to our data. Variant chr6-151808349-C-A is described in ClinVar as Benign. ClinVar VariationId is 3341627.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

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.437C>A	p.Pro146Gln	missense	Exon 1 of 8	NP_000116.2	P03372-1
	ESR1	NM_001291230.2		c.437C>A	p.Pro146Gln	missense	Exon 2 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.437C>A	p.Pro146Gln	missense	Exon 2 of 9	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.437C>A	p.Pro146Gln	missense	Exon 1 of 8	ENSP00000206249.3	P03372-1
	ESR1	ENST00000406599.5	TSL:1	c.437C>A	p.Pro146Gln	missense	Exon 1 of 4	ENSP00000384064.1	Q9H2M1
	ESR1	ENST00000456483.3	TSL:1	c.437C>A	p.Pro146Gln	missense	Exon 1 of 5	ENSP00000415934.3	Q9H2M2

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

GnomAD2 exomes AF: 0.00585 AC: 802 AN: 137080 AF XY: 0.00516

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 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

African (AFR) AF: 0.000296 AC: 9 AN: 30424

American (AMR) AF: 0.0187 AC: 620 AN: 33158

Ashkenazi Jewish (ASJ) AF: 0.000273 AC: 6 AN: 21940

East Asian (EAS) AF: 0.0401 AC: 1435 AN: 35828

South Asian (SAS) AF: 0.00177 AC: 131 AN: 73842

European-Finnish (FIN) AF: 0.0000499 AC: 2 AN: 40102

Middle Eastern (MID) AF: 0.000249 AC: 1 AN: 4022

European-Non Finnish (NFE) AF: 0.0000544 AC: 58 AN: 1067028

Other (OTH) AF: 0.00191 AC: 107 AN: 56020

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

African (AFR) AF: 0.000424 AC: 17 AN: 40052

American (AMR) AF: 0.0175 AC: 260 AN: 14846

Ashkenazi Jewish (ASJ) AF: 0.000868 AC: 3 AN: 3458

East Asian (EAS) AF: 0.0278 AC: 137 AN: 4922

South Asian (SAS) AF: 0.00232 AC: 11 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10424

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67754

Other (OTH) AF: 0.00385 AC: 8 AN: 2078

Alfa AF: 0.00202 Hom.: 5

Bravo AF: 0.00357

ExAC AF: 0.00351 AC: 395

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.9
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		0.93	P
Vest4		0.30
MVP		0.53
MPC		1.1
ClinPred		0.044	T
GERP RS		4.9
Varity_R		0.14
gMVP		0.37
Mutation Taster		=89/11	polymorphism

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