chr6-151808349-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000125.4(ESR1):​c.437C>T​(p.Pro146Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000294 in 1,362,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P146Q) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.418346).

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.437C>T	p.Pro146Leu	missense	Exon 1 of 8	NP_000116.2
	ESR1	NM_001291230.2		c.437C>T	p.Pro146Leu	missense	Exon 2 of 9	NP_001278159.1
	ESR1	NM_001122740.2		c.437C>T	p.Pro146Leu	missense	Exon 2 of 9	NP_001116212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESR1	ENST00000206249.8	TSL:1 MANE Select	c.437C>T	p.Pro146Leu	missense	Exon 1 of 8	ENSP00000206249.3
	ESR1	ENST00000406599.5	TSL:1	c.437C>T	p.Pro146Leu	missense	Exon 1 of 4	ENSP00000384064.1
	ESR1	ENST00000456483.3	TSL:1	c.437C>T	p.Pro146Leu	missense	Exon 1 of 5	ENSP00000415934.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000730 AC: 1 AN: 137080 AF XY: 0.0000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000166

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1362382 Hom.: 0 Cov.: 37 AF XY: 0.00000299 AC XY: 2 AN XY: 668850

African (AFR) AF: 0.00 AC: 0 AN: 30424

American (AMR) AF: 0.00 AC: 0 AN: 33166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21940

East Asian (EAS) AF: 0.00 AC: 0 AN: 35832

South Asian (SAS) AF: 0.00 AC: 0 AN: 73846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4022

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1067028

Other (OTH) AF: 0.00 AC: 0 AN: 56020

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000889 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Benign	-0.075
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.1	L
PhyloP100		5.9
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.17
Sift	Uncertain	0.024	D
Sift4G	Benign	0.078	T
Polyphen		0.013	B
Vest4		0.34
MutPred		0.68		Gain of MoRF binding (P = 0.0737)
MVP		0.48
MPC		0.53
ClinPred		0.67	D
GERP RS		4.9
Varity_R		0.15
gMVP		0.41
Mutation Taster		=85/15	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;