chr3-57198280-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_003865.3(HESX1):c.475C>T(p.Arg159Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,612,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
HESX1
NM_003865.3 missense
NM_003865.3 missense
Scores
11
2
1
Clinical Significance
Conservation
PhyloP100: 3.78
Genes affected
HESX1 (HGNC:4877): (HESX homeobox 1) This gene encodes a conserved homeobox protein that is a transcriptional repressor in the developing forebrain and pituitary gland. Mutations in this gene are associated with septooptic dysplasia, HESX1-related growth hormone deficiency, and combined pituitary hormone deficiency. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
?
In a helix (size 15) in uniprot entity HESX1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003865.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.949
PP5
?
Variant 3-57198280-G-A is Pathogenic according to our data. Variant chr3-57198280-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1206790.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HESX1 | NM_003865.3 | c.475C>T | p.Arg159Trp | missense_variant | 4/4 | ENST00000295934.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HESX1 | ENST00000295934.8 | c.475C>T | p.Arg159Trp | missense_variant | 4/4 | 1 | NM_003865.3 | P1 | |
HESX1 | ENST00000647958.1 | c.475C>T | p.Arg159Trp | missense_variant | 7/7 | P1 | |||
HESX1 | ENST00000473921.2 | c.373C>T | p.Arg125Trp | missense_variant | 3/3 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 151970Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 250890Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135760
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GnomAD4 exome AF: 0.000156 AC: 228AN: 1460604Hom.: 0 Cov.: 30 AF XY: 0.000150 AC XY: 109AN XY: 726654
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Septo-optic dysplasia sequence Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 20, 2021 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 02, 2021 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2023 | Published functional studies demonstrate the p.R159W variant disrupts normal protein function (Fang et al., 2016; Pozzi et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28396770, 27000987, 31395954) - |
Septo-optic dysplasia sequence;C2750027:Growth hormone deficiency with pituitary anomalies Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects HESX1 function (PMID: 27000987, 28396770). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 1206790). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 159 of the HESX1 protein (p.Arg159Trp). This variant is present in population databases (rs770886420, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of septo-optic dysplasia (PMID: 2700987, 28396770, 31395954). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
Polyphen
D;D;.
Vest4
0.91, 0.87
MVP
0.99
MPC
0.37
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at