3-57198276-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM5PP3_StrongPP5

The NM_003865.3(HESX1):c.479G>A(p.Arg160His) variant causes a missense change. The variant allele was found at a frequency of 0.000031 in 1,612,832 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R160C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 6.00

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 9 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

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-57198277-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7691.Status of the report is no_assertion_criteria_provided, 0 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 3-57198276-C-T is Pathogenic according to our data. Variant chr3-57198276-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 985575.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HESX1	NM_003865.3 linkuse as main transcript	c.479G>A	p.Arg160His	missense_variant	4/4	ENST00000295934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HESX1	ENST00000295934.8 linkuse as main transcript	c.479G>A	p.Arg160His	missense_variant	4/4	1	NM_003865.3	P1
HESX1	ENST00000647958.1 linkuse as main transcript	c.479G>A	p.Arg160His	missense_variant	7/7			P1
HESX1	ENST00000473921.2 linkuse as main transcript	c.377G>A	p.Arg126His	missense_variant	3/3	5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250942

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135760

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1460858

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726724

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

151974

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74228

show subpopulations

Gnomad4 AFR

AF:

0.0000484

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2018

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 07, 2022

Seen in the heterozygous state in a patient with panhypopituitarism and inherited from an unaffected father; patient did not have an identifiable second variant in HESX1 but also had a variant in the PROP1 gene (Blum et al., 2018); Published functional studies demonstrate that R160H significantly impaired the role of HESX1 as a transcriptional repressor (Fang et al., 2016); This variant is associated with the following publications: (PMID: 25500790, 30487145, 22145475, 27000987, 30266296, 32621723) -

Septo-optic dysplasia sequence;C2750027:Growth hormone deficiency with pituitary anomalies

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 160 of the HESX1 protein (p.Arg160His). This variant is present in population databases (rs766234350, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of septo-optic dysplasia (PMID: 22145475, 25500790, 27000987, 30266296). ClinVar contains an entry for this variant (Variation ID: 985575). 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. Experimental studies have shown that this missense change affects HESX1 function (PMID: 27000987). This variant disrupts the p.Arg160 amino acid residue in HESX1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9620767, 19093031). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

D;D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.98

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.90

MutationAssessor

Pathogenic

4.3

H;H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.66

Polyphen

1.0

D;D;.

Vest4

0.84, 0.88

MutPred

0.96

Loss of MoRF binding (P = 0.061);Loss of MoRF binding (P = 0.061);.;

MVP

1.0

MPC

0.36

ClinPred

1.0

GERP RS

5.3

Varity_R

0.97

gMVP

0.89

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