rs397509428

Positions:

• chr6-152011684-G-T

Variant summary

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

The ENST00000206249.8(ESR1):​c.1125G>T​(p.Gln375His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ESR1 ENST00000206249.8 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 1.10

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 ENST00000206249.8
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 6-152011684-G-T is Pathogenic according to our data. Variant chr6-152011684-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 60557.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESR1	NM_000125.4	c.1125G>T	p.Gln375His	missense_variant	5/8	ENST00000206249.8	NP_000116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESR1	ENST00000206249.8	c.1125G>T	p.Gln375His	missense_variant	5/8	1	NM_000125.4	ENSP00000206249	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Estrogen resistance syndrome Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 11, 2013	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;D;D;D;D;D
Eigen	Benign	0.15
Eigen_PC	Benign	0.053
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	.;.;D;.;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Uncertain	-0.051	T
MutationAssessor	Pathogenic	3.6	H;H;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D;D;D;D;.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;.;.
Vest4		0.97
MutPred		0.90		Loss of catalytic residue at Q375 (P = 0.0226);Loss of catalytic residue at Q375 (P = 0.0226);Loss of catalytic residue at Q375 (P = 0.0226);Loss of catalytic residue at Q375 (P = 0.0226);.;.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		-0.86
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 14

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397509428; hg19: chr6-152332819;