3-57198280-G-A

Variant names:

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:2

Conservation

PhyloP100: 3.78

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]

HESX1 links:

Genome browser will be placed here

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: {Likely_pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HESX1	NM_003865.3 link	c.475C>T	p.Arg159Trp	missense_variant	Exon 4 of 4	ENST00000295934.8	NP_003856.1	Q9UBX0A1LQR0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HESX1	ENST00000295934.8 link	c.475C>T	p.Arg159Trp	missense_variant	Exon 4 of 4	1	NM_003865.3	ENSP00000295934.3	Q9UBX0
HESX1	ENST00000647958.1 link	c.475C>T	p.Arg159Trp	missense_variant	Exon 7 of 7			ENSP00000498190.1	Q9UBX0
HESX1	ENST00000473921.2 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 3 of 3	5		ENSP00000418918.1	C9J0A9

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151970

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

250890

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000156

AC:

228

AN:

1460604

Hom.:

Cov.:

AF XY:

0.000150

AC XY:

109

AN XY:

726654

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:

0.000203

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151970

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74222

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.00111

Hom.:

Bravo

AF:

0.0000416

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Septo-optic dysplasia sequence

Pathogenic:2Uncertain:1

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 02, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 20, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

HESX1-Related Disorders

Pathogenic:1

Oct 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HESX1 c.475C>T (p.Arg159Trp) results in a non-conservative amino acid change located in the Homeodomain (Homeodomain) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 250890 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.475C>T has been reported in the literature in at least one compound heterozygous individual affected with Combined Pituitary Hormone Deficiency and pituitary aplasia (e.g., Fang_2016). The variant has also been reported in a heterozygous individual with Septooptic dysplasia, however a second HESX1 variant was not described and segregation of the variant with disease was not demonstrated (e.g., Wojcik_2019, Pozzi_2017). At least two publications report experimental evidence evaluating an impact on protein function, demonstrating that the variant results in altered localization, reduced protein expresssion, and altered or abolished repressor activity, possibly due to altered DNA binding abilities (e.g., Fang_2016, Pozzi_2017). The following publications have been ascertained in the context of this evaluation (PMID: 27000987, 28396770, 31395954). ClinVar contains an entry for this variant (Variation ID: 1206790). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided

Pathogenic:1

Apr 08, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate the p.R159W variant disrupts normal protein function (PMID: 27000987, 28396770); 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, 31395954, 27000987) -

HESX1-related disorder

Pathogenic:1

Sep 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The HESX1 c.475C>T variant is predicted to result in the amino acid substitution p.Arg159Trp. The variant c.475C>T has been identified in the compound heterozygous state in a patient with pituitary aplasia (PA) and combined pituitary hormone deficiency (CPHD, Fang et al. 2016. PMID: 27000987). Additionally, this particular variant has been reported in the heterozygous state in a patient with septo-optic dysplasia (SOD) and his mother who is asymptomatic despite carrying the same variant, suggesting reduced penetrance of this variant (Pozzi et al. 2017. PMID: 28396770; Supplementary Table 3c, Wojcik et al. 2019. PubMed ID: 31395954). Functional analysis in this study showed that the p.Arg159Trp substitution may reduce the expression of HESX1 protein and impair its DNA binding properties (Pozzi et al. 2017. PMID: 28396770). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Septo-optic dysplasia sequence;C2750027:GROWTH HORMONE DEFICIENCY WITH PITUITARY ANOMALIES

Uncertain:1

Sep 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 missense change has been observed in individual(s) with clinical features of septo-optic dysplasia (PMID: 2700987, 28396770, 31395954). This variant is present in population databases (rs770886420, gnomAD 0.004%). 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

.;T;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.5

H;H;.

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-7.5

.;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

.;D;D

Sift4G

Pathogenic

0.0010

.;D;D

Polyphen

1.0

D;D;.

Vest4

0.91, 0.87

MVP

0.99

MPC

0.37

ClinPred

1.0

GERP RS

4.4

Varity_R

0.94

gMVP

0.85

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over