3-57198405-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_003865.3(HESX1):c.445G>A(p.Glu149Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,597,630 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 Pathogenic (no stars).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000083 ( 0 hom. )
Consequence
HESX1
NM_003865.3 missense
NM_003865.3 missense
Scores
10
3
1
Clinical Significance
Conservation
PhyloP100: 6.06
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, 0.984
PP5
?
Variant 3-57198405-C-T is Pathogenic according to our data. Variant chr3-57198405-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7699.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HESX1 | NM_003865.3 | c.445G>A | p.Glu149Lys | missense_variant | 3/4 | ENST00000295934.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HESX1 | ENST00000295934.8 | c.445G>A | p.Glu149Lys | missense_variant | 3/4 | 1 | NM_003865.3 | P1 | |
HESX1 | ENST00000647958.1 | c.445G>A | p.Glu149Lys | missense_variant | 6/7 | P1 | |||
HESX1 | ENST00000473921.2 | c.358-110G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152128Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250620Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135654
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GnomAD4 exome AF: 0.00000830 AC: 12AN: 1445502Hom.: 0 Cov.: 28 AF XY: 0.00000972 AC XY: 7AN XY: 720406
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74318
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Growth hormone deficiency with pituitary anomalies Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 01, 2007 | - - |
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
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
Polyphen
D;D
Vest4
0.95
MutPred
Gain of MoRF binding (P = 0.0118);Gain of MoRF binding (P = 0.0118);
MVP
0.98
MPC
0.38
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