rs28936703

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003865.3(HESX1):c.509C>T(p.Ser170Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000608 in 1,613,136 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:3

Conservation

PhyloP100: 5.80

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

septooptic dysplasia
Inheritance: AD, AR Classification: STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet
combined pituitary hormone deficiencies, genetic form
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hypothyroidism due to deficient transcription factors involved in pituitary development or function
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
pituitary stalk interruption syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HESX1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HESX1	NM_003865.3 link	c.509C>T	p.Ser170Leu	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.509C>T	p.Ser170Leu	missense_variant	Exon 4 of 4	1	NM_003865.3	ENSP00000295934.3	Q9UBX0
HESX1	ENST00000647958.1 link	c.509C>T	p.Ser170Leu	missense_variant	Exon 7 of 7			ENSP00000498190.1	Q9UBX0
HESX1	ENST00000473921.2 link	c.407C>T	p.Ser136Leu	missense_variant	Exon 3 of 3	5		ENSP00000418918.1	C9J0A9

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251076

AF XY:

0.0000295

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 FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1460978

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

726786

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

86168

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000810

AC:

AN:

1111466

Other (OTH)

AF:

0.0000994

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.428

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41516

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67988

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000752

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SEPTOOPTIC DYSPLASIA, MILD

Pathogenic:1

Jan 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

HESX1-related disorder

Pathogenic:1

Mar 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The HESX1 c.509C>T variant is predicted to result in the amino acid substitution p.Ser170Leu. This variant was reported in multiple heterozygous individuals with isolated growth hormone deficiency, one of whom also had optic hypoplasia (Parks et al 1999. PubMed ID: 10599689; Brickman et al. 2001. PubMed ID: 11748154). This variant was also reported in a heterozygous individual with ventriculomegaly, partial agenesis of the corpus collosum, cavum septum pellucidum, adrenal gland agenesis, aplasia/hypoplasia of the optic tract, and optic nerve aplasia (Marangoni et al. 2021. PubMed ID: 34906519). Results of DNA binding assays suggest the p.Ser170Leu variant in heterozygous individuals is functionally compromised (Thomas et al. 2001. PubMed ID: 11136712; Brickman et al. 2001. PubMed ID: 11748154). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as likely pathogenic. -

not provided

Uncertain:1

Oct 26, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Aug 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: 11136712, 11748154). 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: 7692). This missense change has been observed in individual(s) with clinical features of autosomal dominant septo-optic dysplasia (PMID: 11136712, 11748154, 17148560, 34906519). This variant is present in population databases (rs28936703, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 170 of the HESX1 protein (p.Ser170Leu). -

Septo-optic dysplasia sequence

Uncertain:1

Oct 10, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ser170Leu variant in the HESX1 gene has been previously reported in multiple unrelated individuals with clinical features of autosomal dominant HESX1-related disorders, including isolated growth hormone deficiency (Parks 1999, Brickman 2001, Thomas 2001). The p.Ser170Leu variant has been submitted to ClinVar (Variation ID: 7692, ncbi.nlm.nih.gov/clinvar/), and has been identified in 9/251076 (v4.0.0: 98/1613136) chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This allele frequency is low enough to be consistent with a milder hypomorphic allele. In silico tools predict that the p.Ser170Leu variant is deleterious. Functional studies of this variant are supportive of a deleterious effect to the protein; however, it is unclear if this would be sufficient to be disease-causing (Brickman 2001, Thomas 2001). Using ACMG guidelines, this variant was classified as a variant of uncertain significance (ACMG evidence codes used: PS3_moderate, PS4_supporting). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

D;D;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.67

D;D;D

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

1.1

L;L;.

PhyloP100

5.8

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.2

.;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.035

.;D;D

Polyphen

0.97

D;D;.

Vest4

0.51, 0.89

MVP

0.97

MPC

0.20

ClinPred

0.64

GERP RS

4.6

Varity_R

0.30

gMVP

0.55

Mutation Taster

=9/91

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs28936703

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over