rs9878928

chr3-57198476-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_003865.3(HESX1):c.374A>G(p.Asn125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.013 in 1,589,044 control chromosomes in the GnomAD database, including 2,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N125G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.070 ( 1245 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 1004 hom. )

Consequence

HESX1
NM_003865.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.44

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 Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.0017352402).

BP6

Variant 3-57198476-T-C is Benign according to our data. Variant chr3-57198476-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 282975.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-57198476-T-C is described in Lovd as [Benign]. Variant chr3-57198476-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HESX1	NM_003865.3 linkuse as main transcript	c.374A>G	p.Asn125Ser	missense_variant	3/4	ENST00000295934.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
HESX1	ENST00000295934.8 linkuse as main transcript	c.374A>G	p.Asn125Ser	missense_variant	3/4	1	NM_003865.3	P1
HESX1	ENST00000647958.1 linkuse as main transcript	c.374A>G	p.Asn125Ser	missense_variant	6/7			P1
HESX1	ENST00000473921.2 linkuse as main transcript	c.358-181A>G		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0696

AC:

10584

AN:

152130

Hom.:

1240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.240

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0289

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.0549

GnomAD3 exomes

AF:

0.0179

AC:

4419

AN:

247290

Hom.:

453

AF XY:

0.0131

AC XY:

1759

AN XY:

133786

show subpopulations

Gnomad AFR exome

AF:

0.238

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000374

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000773

Gnomad OTH exome

AF:

0.00732

GnomAD4 exome

AF:

0.00697

AC:

10019

AN:

1436796

Hom.:

1004

Cov.:

AF XY:

0.00606

AC XY:

4342

AN XY:

716234

show subpopulations

Gnomad4 AFR exome

AF:

0.238

Gnomad4 AMR exome

AF:

0.0148

Gnomad4 ASJ exome

AF:

0.00525

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000496

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000409

Gnomad4 OTH exome

AF:

0.0161

GnomAD4 genome

AF:

0.0698

AC:

10624

AN:

152248

Hom.:

1245

Cov.:

AF XY:

0.0690

AC XY:

5137

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.240

Gnomad4 AMR

AF:

0.0289

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.0543

Alfa

AF:

0.0120

Hom.:

368

Bravo

AF:

0.0786

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.222

AC:

974

ESP6500EA

AF:

0.00140

AC:

ExAC

AF:

0.0217

AC:

2639

Asia WGS

AF:

0.0130

AC:

AN:

3470

EpiCase

AF:

0.00147

EpiControl

AF:

0.000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 11748154, 19844116, 20981092, 21228398, 10599689, 27884173, 27013732, 25910213) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2015	- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Combined Pituitary Hormone Deficiency, Dominant/Recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Septo-optic dysplasia sequence

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.28

Cadd

Benign

Dann

Benign

0.95

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.77

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.070

N;N

MutationTaster

Benign

0.00063

P;P

PrimateAI

Uncertain

0.57

Polyphen

0.074

B;B

Vest4

0.060

MPC

0.052

ClinPred

0.012

GERP RS

4.4

Varity_R

0.079

gMVP

0.26

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