rs768165720

chr3-57198784-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1

The NM_003865.3(HESX1):c.326G>A(p.Arg109Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000744 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 5.72

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 Uncertain_significance. Variant got 2 ACMG points.

PM1

In a DNA_binding_region Homeobox (size 59) in uniprot entity HESX1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_003865.3

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HESX1	NM_003865.3 linkuse as main transcript	c.326G>A	p.Arg109Gln	missense_variant	2/4	ENST00000295934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HESX1	ENST00000295934.8 linkuse as main transcript	c.326G>A	p.Arg109Gln	missense_variant	2/4	1	NM_003865.3	P1
HESX1	ENST00000647958.1 linkuse as main transcript	c.326G>A	p.Arg109Gln	missense_variant	5/7			P1
HESX1	ENST00000473921.2 linkuse as main transcript	c.326G>A	p.Arg109Gln	missense_variant	2/3	5
HESX1	ENST00000495160.2 linkuse as main transcript			downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000986

AC:

AN:

152118

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:

0.000221

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000756

AC:

AN:

251306

Hom.:

AF XY:

0.0000810

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000718

AC:

105

AN:

1461850

Hom.:

Cov.:

AF XY:

0.0000784

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000202

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000719

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000986

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000221

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000284

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.000132

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2019	A published functional study suggests impaired protein function with reduced DNA binding ability and impaired ability to repress PROP-mediatd activation, however, the significance of these results are uncertain (Takagi et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 14558921, 26781211, 28332357, 9100579) -

Male infertility with spermatogenesis disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Sep 01, 2023

- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 497545). This missense change has been observed in individual(s) with clinical features of septo-optic dysplasia (PMID: 26781211, 28332357). This variant is present in population databases (rs768165720, gnomAD 0.02%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 109 of the HESX1 protein (p.Arg109Gln). -

Septo-optic dysplasia sequence

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant p.R109Q in HESX1 (NM_003865.3) has been previously reported in heterozygous state in an affected Japanese child. Functional studies revealed a damaging effect (Takagi M et al). The variant has been submitted to ClinVar as Uncertain Significance. The missense variant c.326G>A (p.R109Q) in HESX1 (NM_003865.3) is observed in 4/18394 (0.0217%) alleles from individuals of East Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. The p.R109Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 109 of HESX1 is conserved in all mammalian species. The nucleotide c.326 in HESX1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.32

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.69

D;D;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Uncertain

0.97

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.71

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

Polyphen

1.0

D;D;.

Vest4

0.83, 0.96

MutPred

0.62

Loss of MoRF binding (P = 0.0422);Loss of MoRF binding (P = 0.0422);Loss of MoRF binding (P = 0.0422);

MVP

0.97

MPC

0.25

ClinPred

0.60

GERP RS

5.7

Varity_R

0.91

gMVP

0.71

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

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