rs143057250

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_003865.3(HESX1):c.385G>A(p.Val129Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000937 in 1,601,096 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00097 ( 2 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 2.06

Publications

6 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029887676).

BP6

Variant 3-57198465-C-T is Benign according to our data. Variant chr3-57198465-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 267733.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000664 (101/152186) while in subpopulation NFE AF = 0.0011 (75/68014). AF 95% confidence interval is 0.000902. There are 0 homozygotes in GnomAd4. There are 51 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HESX1	NM_003865.3 link	c.385G>A	p.Val129Ile	missense_variant	Exon 3 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.385G>A	p.Val129Ile	missense_variant	Exon 3 of 4	1	NM_003865.3	ENSP00000295934.3	Q9UBX0
HESX1	ENST00000647958.1 link	c.385G>A	p.Val129Ile	missense_variant	Exon 6 of 7			ENSP00000498190.1	Q9UBX0
HESX1	ENST00000473921.2 link	c.358-170G>A		intron_variant	Intron 2 of 2	5		ENSP00000418918.1	C9J0A9

Frequencies

GnomAD3 genomes

AF:

0.000664

AC:

101

AN:

152068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000810

AC:

202

AN:

249392

AF XY:

0.000815

show subpopulations

Gnomad AFR exome

AF:

0.000252

Gnomad AMR exome

AF:

0.000583

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000494

GnomAD4 exome

AF:

0.000966

AC:

1400

AN:

1448910

Hom.:

Cov.:

AF XY:

0.000909

AC XY:

656

AN XY:

721554

show subpopulations

African (AFR)

AF:

0.000242

AC:

AN:

33014

American (AMR)

AF:

0.000517

AC:

AN:

44512

Ashkenazi Jewish (ASJ)

AF:

0.00223

AC:

AN:

26046

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.000199

AC:

AN:

85398

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53346

Middle Eastern (MID)

AF:

0.000722

AC:

AN:

5544

European-Non Finnish (NFE)

AF:

0.00112

AC:

1234

AN:

1101602

Other (OTH)

AF:

0.000885

AC:

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

122

182

243

304

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000664

AC:

101

AN:

152186

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41518

American (AMR)

AF:

0.000392

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68014

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000786

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00187

AC:

ExAC

AF:

0.000791

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3470

EpiCase

AF:

0.00131

EpiControl

AF:

0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Septo-optic dysplasia sequence

Uncertain:3Benign:1

Apr 28, 2009

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2016

Hehr Laboratory, Center for Human Genetics Regensburg

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided

Uncertain:2Benign:2

Feb 15, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pituitary hormone deficiency, combined, 1

Uncertain:1

Apr 28, 2009

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Amenorrhea

Uncertain:1

Mar 08, 2021

Yale Center for Mendelian Genomics, Yale University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

Uncertain:1

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 129 of the HESX1 protein (p.Val129Ile). This variant is present in population databases (rs143057250, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of HESX1-related conditions (PMID: 36531499). ClinVar contains an entry for this variant (Variation ID: 267733). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases

Benign:1

Dec 24, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

HESX1-related disorder

Benign:1

May 12, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

D;D

Eigen

Benign

0.15

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.61

.;T

M_CAP

Benign

0.057

MetaRNN

Benign

0.030

T;T

MetaSVM

Uncertain

0.48

MutationAssessor

Benign

0.075

N;N

PhyloP100

2.1

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.73

.;N

REVEL

Uncertain

0.49

Sift

Benign

0.070

.;T

Sift4G

Benign

0.11

.;T

Polyphen

0.92

P;P

Vest4

0.15

MVP

0.91

MPC

0.074

ClinPred

0.031

GERP RS

3.8

Varity_R

0.10

gMVP

0.38

Mutation Taster

=72/28

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over