chr3-57198476-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_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. 13/21 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:9

Conservation

PhyloP100: 1.44

Publications

16 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 -20 ACMG points.

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.

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 rank	MANE	Protein	UniProt
HESX1	NM_003865.3 link	c.374A>G	p.Asn125Ser	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.374A>G	p.Asn125Ser	missense_variant	Exon 3 of 4	1	NM_003865.3	ENSP00000295934.3	Q9UBX0
HESX1	ENST00000647958.1 link	c.374A>G	p.Asn125Ser	missense_variant	Exon 6 of 7			ENSP00000498190.1	Q9UBX0
HESX1	ENST00000473921.2 link	c.358-181A>G		intron_variant	Intron 2 of 2	5		ENSP00000418918.1	C9J0A9

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

GnomAD2 exomes

AF:

0.0179

AC:

4419

AN:

247290

AF XY:

0.0131

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 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

African (AFR)

AF:

0.238

AC:

7708

AN:

32362

American (AMR)

AF:

0.0148

AC:

654

AN:

44110

Ashkenazi Jewish (ASJ)

AF:

0.00525

AC:

136

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39476

South Asian (SAS)

AF:

0.000496

AC:

AN:

84750

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53328

Middle Eastern (MID)

AF:

0.0138

AC:

AN:

5422

European-Non Finnish (NFE)

AF:

0.000409

AC:

447

AN:

1091958

Other (OTH)

AF:

0.0161

AC:

956

AN:

59476

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

392

784

1177

1569

1961

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<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:

0.0698

AC:

10624

AN:

152248

Hom.:

1245

Cov.:

AF XY:

0.0690

AC XY:

5137

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.240

AC:

9959

AN:

41508

American (AMR)

AF:

0.0289

AC:

442

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00145

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00110

AC:

AN:

68020

Other (OTH)

AF:

0.0543

AC:

115

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

406

811

1217

1622

2028

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0234

Hom.:

1036

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:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 11748154, 19844116, 20981092, 21228398, 10599689, 27884173, 27013732, 25910213) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 02, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined Pituitary Hormone Deficiency, Dominant/Recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Septo-optic dysplasia sequence

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.52

D;D

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

.;D

MetaRNN

Benign

0.0017

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.070

N;N

PhyloP100

1.4

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.3

.;N

REVEL

Uncertain

0.35

Sift

Benign

0.43

.;T

Sift4G

Benign

0.51

.;T

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

Mutation Taster

=90/10

polymorphism (auto)

(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