rs1131692059

Positions:

• chr6-152011740-G-A
• chr6-152011740-G-C
• chr6-152011740-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000125.4(ESR1):​c.1181G>A​(p.Arg394His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ESR1 NM_000125.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 9.60

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 Likely_pathogenic. Variant got 9 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 6-152011740-G-A is Pathogenic according to our data. Variant chr6-152011740-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430713.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESR1	NM_000125.4	c.1181G>A	p.Arg394His	missense_variant	5/8	ENST00000206249.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESR1	ENST00000206249.8	c.1181G>A	p.Arg394His	missense_variant	5/8	1	NM_000125.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461180 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726900

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Estrogen resistance syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 03, 2018	- -
Likely pathogenic, no assertion criteria provided	literature only	SIB Swiss Institute of Bioinformatics	Mar 24, 2017	The variant is absent from the ExAC database, it consegregates with disease phenotype, it is highly conserved and located in the steroid binding region of the estrogen receptor. It is predicted to be disease causing by MutationTaster. Functional studies show decreased estrogen receptor activity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D;D;D;D;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.91
MutPred		0.90		Gain of catalytic residue at W393 (P = 0.0918);Gain of catalytic residue at W393 (P = 0.0918);Gain of catalytic residue at W393 (P = 0.0918);Gain of catalytic residue at W393 (P = 0.0918);.;.;
MVP		0.98
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.95
gMVP		0.97

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: rs1131692059; hg19: chr6-152332875; COSMIC: COSV52798756;