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GeneBe

3-57198400-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_003865.3(HESX1):c.450C>G(p.Asp150Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,441,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

2
8
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HESX1NM_003865.3 linkuse as main transcriptc.450C>G p.Asp150Glu missense_variant 3/4 ENST00000295934.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HESX1ENST00000295934.8 linkuse as main transcriptc.450C>G p.Asp150Glu missense_variant 3/41 NM_003865.3 P1
HESX1ENST00000647958.1 linkuse as main transcriptc.450C>G p.Asp150Glu missense_variant 6/7 P1
HESX1ENST00000473921.2 linkuse as main transcriptc.358-105C>G intron_variant 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000208
AC:
3
AN:
1441890
Hom.:
0
Cov.:
27
AF XY:
0.00000278
AC XY:
2
AN XY:
718768
show subpopulations
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:
0.00000274
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Septo-optic dysplasia sequence Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMoosajee Lab, UCL Institute of Ophthalmology-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.080
Cadd
Benign
23
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.44
T;T
Eigen
Benign
-0.025
Eigen_PC
Benign
0.064
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Uncertain
0.22
D
MetaRNN
Uncertain
0.67
D;D
MetaSVM
Uncertain
0.26
D
MutationAssessor
Benign
0.40
N;N
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.72
T
Polyphen
1.0
D;D
Vest4
0.56
MutPred
0.42
Loss of MoRF binding (P = 0.1225);Loss of MoRF binding (P = 0.1225);
MVP
0.94
MPC
0.32
ClinPred
0.89
D
GERP RS
3.7
Varity_R
0.23
gMVP
0.53

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1385826685; hg19: chr3-57232428; API