rs144792551

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001366110.1(PAX4):c.313C>T(p.Arg105Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,614,152 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00077 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 3 hom. )

Consequence

PAX4
NM_001366110.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 2.14

Publications

8 publications found

Variant links:

Genes affected

PAX4 (HGNC:8618): (paired box 4) This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. The paired box 4 gene is involved in pancreatic islet development and mouse studies have demonstrated a role for this gene in differentiation of insulin-producing beta cells. [provided by RefSeq, Jul 2008]

PAX4 Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
diabetes mellitus, noninsulin-dependent
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
maturity-onset diabetes of the young type 9
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
monogenic diabetes
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

PAX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 117 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 5 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 3 of 10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 link	c.313C>T	p.Arg105Cys	missense_variant	Exon 5 of 12	5	NM_001366110.1	ENSP00000491782.1

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00249

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00107

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000664

AC:

167

AN:

251418

AF XY:

0.000780

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.00116

AC:

1697

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00120

AC XY:

871

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000358

AC:

AN:

33478

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00129

AC:

111

AN:

86258

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00136

AC:

1507

AN:

1112006

Other (OTH)

AF:

0.000861

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

103

206

310

413

516

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

192

256

320

<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:

0.000768

AC:

117

AN:

152268

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41552

American (AMR)

AF:

0.000131

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00249

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00107

AC:

AN:

68028

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00105

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000634

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 97 of the PAX4 protein (p.Arg97Cys). This variant is present in population databases (rs144792551, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PAX4-related conditions. ClinVar contains an entry for this variant (Variation ID: 358806). 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 disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Jan 03, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PAX4-related disorder

Uncertain:1

Feb 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PAX4 c.289C>T variant is predicted to result in the amino acid substitution p.Arg97Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.15% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Maturity onset diabetes mellitus in young

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Sep 01, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:PP3 (8 predictors), BP4 (2 predictors),BS2 (10 cases and 8 controls in type2diabetesgenetics.org). NOTE: Illumina and Chicago call it a VUS. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.64

.;.;.;.;.;D

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.33

LIST_S2

Pathogenic

0.98

D;D;D;D;.;D

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.036

T;T;T;T;T;T

MetaSVM

Pathogenic

1.0

PhyloP100

2.1

PrimateAI

Benign

0.33

PROVEAN

Benign

-2.2

N;.;N;N;N;.

REVEL

Uncertain

0.55

Sift

Pathogenic

0.0

D;.;D;D;D;.

Sift4G

Uncertain

0.0020

D;.;.;D;D;D

Polyphen

0.99

D;.;.;.;D;.

Vest4

0.57

MVP

0.93

MPC

0.34

ClinPred

0.056

GERP RS

4.7

gMVP

0.41

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.32

Position offset: -47

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