rs121909173

Positions:

chr3-57199901-C-G

Variant summary

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

The NM_003865.3(HESX1):c.18G>C(p.Gln6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,854 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: 0.000031 ( 0 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:2

Conservation

PhyloP100: 0.346

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HESX1	NM_003865.3 linkuse as main transcript	c.18G>C	p.Gln6His	missense_variant	1/4	ENST00000295934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HESX1	ENST00000295934.8 linkuse as main transcript	c.18G>C	p.Gln6His	missense_variant	1/4	1	NM_003865.3	P1
HESX1	ENST00000647958.1 linkuse as main transcript	c.18G>C	p.Gln6His	missense_variant	4/7			P1
HESX1	ENST00000473921.2 linkuse as main transcript	c.18G>C	p.Gln6His	missense_variant	1/3	5
HESX1	ENST00000495160.2 linkuse as main transcript	c.18G>C	p.Gln6His	missense_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152178

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

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251488

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135916

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:

0.0000527

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000315

AC:

AN:

1461676

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727166

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000351

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

PITUITARY HORMONE DEFICIENCY, COMBINED, 5

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2001

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 11, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17148560, 11136712, 27343026, 31022718, 12424431, 23465708, 21325470, 18852528, 14561704, 26147833, 31589614) -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 31, 2023

This variant is present in population databases (rs121909173, gnomAD 0.004%). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 6 of the HESX1 protein (p.Gln6His). This missense change has been observed in individual(s) with HESX1-related conditions (PMID: 11136712, 18852528, 31022718, 33451138). 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. 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 7700). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.20

T;T;T;T

Eigen

Benign

-0.52

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.60

.;T;T;T

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.70

D;D;D;D

MetaSVM

Uncertain

-0.088

MutationAssessor

Benign

1.7

L;L;.;.

MutationTaster

Benign

0.022

A;A

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.93

.;N;N;N

REVEL

Uncertain

0.53

Sift

Benign

0.057

.;T;T;T

Sift4G

Benign

0.18

.;T;T;T

Polyphen

0.0020

B;B;.;.

Vest4

0.27, 0.21

MutPred

0.68

Gain of catalytic residue at L5 (P = 0.2127);Gain of catalytic residue at L5 (P = 0.2127);Gain of catalytic residue at L5 (P = 0.2127);Gain of catalytic residue at L5 (P = 0.2127);

MVP

0.95

MPC

0.054

ClinPred

0.045

GERP RS

2.9

Varity_R

0.060

gMVP

0.44

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