chr3-57198476-T-C

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

5
13

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

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
HESX1NM_003865.3 linkc.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 Appris UniProt
HESX1ENST00000295934.8 linkc.374A>G p.Asn125Ser missense_variant Exon 3 of 4 1 NM_003865.3 ENSP00000295934.3 Q9UBX0
HESX1ENST00000647958.1 linkc.374A>G p.Asn125Ser missense_variant Exon 6 of 7 ENSP00000498190.1 Q9UBX0
HESX1ENST00000473921.2 linkc.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.:
32
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.:
27
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:
0
AN:
39476
South Asian (SAS)
AF:
0.000496
AC:
42
AN:
84750
European-Finnish (FIN)
AF:
0.0000188
AC:
1
AN:
53328
Middle Eastern (MID)
AF:
0.0138
AC:
75
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
0
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
0
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.:
32
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:
16
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5184
South Asian (SAS)
AF:
0.00145
AC:
7
AN:
4822
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.0340
AC:
10
AN:
294
European-Non Finnish (NFE)
AF:
0.00110
AC:
75
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
0
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
0
96
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:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.222
AC:
974
ESP6500EA
AF:
0.00140
AC:
12
ExAC
AF:
0.0217
AC:
2639
Asia WGS
AF:
0.0130
AC:
47
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
T
BayesDel_noAF
Benign
-0.28
CADD
Benign
16
DANN
Benign
0.95
DEOGEN2
Uncertain
0.52
D;D
Eigen
Benign
-0.41
Eigen_PC
Benign
-0.18
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Uncertain
0.89
.;D
MetaRNN
Benign
0.0017
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.070
N;N
PhyloP100
1.4
PrimateAI
Uncertain
0.57
T
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
T
GERP RS
4.4
Varity_R
0.079
gMVP
0.26
Mutation Taster
=90/10
polymorphism (auto)

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

Other links and lift over

dbSNP: rs9878928; hg19: chr3-57232504; API