rs1057519714

chr6-152094402-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000125.4(ESR1):c.1387T>C(p.Ser463Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.52

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain NR LBD (size 236) in uniprot entity ESR1_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000125.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-152094402-T-C is Pathogenic according to our data. Variant chr6-152094402-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 375934.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38775685).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.1387T>C	p.Ser463Pro	missense_variant	7/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.1387T>C	p.Ser463Pro	missense_variant	7/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Oct 02, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.39	T;T;T;T;T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	1.7	L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Uncertain	0.53
Sift	Benign	0.22	T;T;T;T;D
Sift4G	Benign	0.14	T;T;T;T;D
Polyphen		0.98	D;D;D;D;B
Vest4		0.18
MutPred		0.45		Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);Gain of relative solvent accessibility (P = 0.09);.;
MVP		0.87
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.92
gMVP		0.84

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: rs1057519714; hg19: chr6-152415537; COSMIC: COSV52784970;