chr7-127615412-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3BP4_StrongBP6BS2

The NM_001366110.1(PAX4):c.133C>T(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,614,168 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 3 hom. )

Consequence

PAX4
NM_001366110.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:3O:1

Conservation

PhyloP100: 2.61

Publications

11 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: Benign. The variant received -8 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.056519568).

BP6

Variant 7-127615412-G-A is Benign according to our data. Variant chr7-127615412-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13792.

BS2

High AC in GnomAd4 at 209 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 4 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 2 of 10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 4 of 12	5	NM_001366110.1	ENSP00000491782.1		A0A1W2PPX4

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

206

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000427

AC:

107

AN:

250682

AF XY:

0.000302

show subpopulations

Gnomad AFR exome

AF:

0.00572

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000155

AC:

226

AN:

1461866

Hom.:

Cov.:

AF XY:

0.000142

AC XY:

103

AN XY:

727232

show subpopulations

African (AFR)

AF:

0.00538

AC:

180

AN:

33474

American (AMR)

AF:

0.000246

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1112008

Other (OTH)

AF:

0.000414

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152302

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00491

AC:

204

AN:

41556

American (AMR)

AF:

0.000196

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

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:

0.000482

Hom.:

Bravo

AF:

0.00149

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000486

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Aug 23, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest a damaging effect, specifically in vitro analyses illustrate a reduction in the PAX4-binding ability to target gene promoters (Mauvais-Jarvis et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32801813, 15509590, 20981092) -

Dec 17, 2019

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

The p.Arg37Trp variant is predicted to substitute the arginine at position 37 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database. -

Oct 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 31, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 20, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Type 2 diabetes mellitus;C2677132:Maturity-onset diabetes of the young type 9

Uncertain:1

Dec 02, 2021

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The heterozygous missense variant c.133C>T (p.Arg45Trp) identified in exon 4 (of 12) of the PAX4 gene has been reported in a patient with Ketosis-prone diabetes (KPD), a rare form of type 2 diabetes, mostly observed in subjects of west Africans and African-Americans (PMID: 15509590). The variant has 0.004851 allele frequency in the African/African American subpopulation represented in the gnomAD(v3.1.2) database (201 heterozygous alleles. Additionally, one homozygous allele in the gnomADv2.1.1 database). This variant is reported as a Variant of Uncertain Significance and benign in the ClinVar database (Variation ID:13792). The variant affects a conserved residue (Arg45) located in the paired box domain of PAX4 gene (PMID: 15509590) and is predicted deleterious by multiple insilico prediction tools (CADD score = 27.9, REVEL score = 0.917). In vitro functional analyses of c.133C>T (p.Arg45Trp) suggested impaired PAX4-binding ability to target gene promoters (PMID: 15509590). Based on the available evidence, the c.133C>T (p.Arg45Trp) variant identified in the PAX4 gene is reported as a Variant of Uncertain Significance. -

Hyperglycemia

Uncertain:1

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Arg45Trp variant is predicted to substitute the arginine at position 45 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database. -

Diabetes mellitus, ketosis-prone, susceptibility to

Other:1

Dec 15, 2004

OMIM

Significance:risk factor

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.55

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

1.0

D;D;D;D

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.057

T;T;T;T

MetaSVM

Pathogenic

0.84

PhyloP100

2.6

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.1

D;.;D;D

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

D;.;D;D

Sift4G

Pathogenic

0.0

D;.;.;D

Polyphen

1.0

D;.;.;.

Vest4

0.89

MVP

1.0

MPC

0.34

ClinPred

0.15

GERP RS

4.8

PromoterAI

-0.037

Neutral

(source)

gMVP

0.54

Mutation Taster

=31/69

disease causing

(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