chr3-57198411-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_003865.3(HESX1):c.439C>A(p.Leu147Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000312 in 1,602,874 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
HESX1
NM_003865.3 missense
NM_003865.3 missense
Scores
5
6
3
Clinical Significance
Conservation
PhyloP100: 2.32
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 8 ACMG points.
PM1
?
In a DNA_binding_region Homeobox (size 59) in uniprot entity HESX1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_003865.3
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.959
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HESX1 | NM_003865.3 | c.439C>A | p.Leu147Ile | missense_variant | 3/4 | ENST00000295934.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HESX1 | ENST00000295934.8 | c.439C>A | p.Leu147Ile | missense_variant | 3/4 | 1 | NM_003865.3 | P1 | |
HESX1 | ENST00000647958.1 | c.439C>A | p.Leu147Ile | missense_variant | 6/7 | P1 | |||
HESX1 | ENST00000473921.2 | c.358-116C>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152078Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000276 AC: 4AN: 1450796Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1AN XY: 722646
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Septo-optic dysplasia sequence;C2750027:Growth hormone deficiency with pituitary anomalies Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 10, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 147 of the HESX1 protein (p.Leu147Ile). 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. 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. This variant has not been reported in the literature in individuals affected with HESX1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.06%). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Uncertain
D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
Polyphen
D;D
Vest4
0.62
MutPred
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP
0.95
MPC
0.37
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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Score
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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