rs2233578

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001366110.1(PAX4):c.421C>T(p.Arg141Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0053 in 1,595,834 control chromosomes in the GnomAD database, including 298 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 161 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 137 hom. )

Consequence

PAX4
NM_001366110.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8O:1

Conservation

PhyloP100: 3.67

Publications

23 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025364459).

BP6

Variant 7-127614497-G-A is Benign according to our data. Variant chr7-127614497-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 13791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0804 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.421C>T	p.Arg141Trp	missense_variant	Exon 6 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.421C>T	p.Arg141Trp	missense_variant	Exon 4 of 10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 link	c.421C>T	p.Arg141Trp	missense_variant	Exon 6 of 12	5	NM_001366110.1	ENSP00000491782.1		A0A1W2PPX4

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

3711

AN:

152082

Hom.:

161

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0829

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0103

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000985

Gnomad OTH

AF:

0.0201

GnomAD2 exomes

AF:

0.00700

AC:

1555

AN:

222208

AF XY:

0.00532

show subpopulations

Gnomad AFR exome

AF:

0.0853

Gnomad AMR exome

AF:

0.00709

Gnomad ASJ exome

AF:

0.00106

Gnomad EAS exome

AF:

0.000238

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.00357

GnomAD4 exome

AF:

0.00328

AC:

4741

AN:

1443634

Hom.:

137

Cov.:

AF XY:

0.00302

AC XY:

2163

AN XY:

716094

show subpopulations

African (AFR)

AF:

0.0867

AC:

2877

AN:

33202

American (AMR)

AF:

0.00731

AC:

310

AN:

42386

Ashkenazi Jewish (ASJ)

AF:

0.00140

AC:

AN:

25704

East Asian (EAS)

AF:

0.000307

AC:

AN:

39092

South Asian (SAS)

AF:

0.000253

AC:

AN:

82878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52380

Middle Eastern (MID)

AF:

0.00788

AC:

AN:

5582

European-Non Finnish (NFE)

AF:

0.000953

AC:

1051

AN:

1102644

Other (OTH)

AF:

0.00653

AC:

390

AN:

59766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

235

470

706

941

1176

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<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:

0.0244

AC:

3715

AN:

152200

Hom.:

161

Cov.:

AF XY:

0.0241

AC XY:

1790

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.0827

AC:

3432

AN:

41494

American (AMR)

AF:

0.0103

AC:

157

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00104

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000985

AC:

AN:

68010

Other (OTH)

AF:

0.0199

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

171

342

513

684

855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.00984

Hom.:

169

Bravo

AF:

0.0282

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.0867

AC:

382

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00751

AC:

910

Asia WGS

AF:

0.00520

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25525159, 27013732, 20981092, 15509590, 16123375) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

Jul 23, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Maturity onset diabetes mellitus in young

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Monogenic diabetes

Benign:1

Sep 22, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:BS1 (9% MAF in Africans in 1000g), BS2 (194 controls and 198 cases in type2diabetesgenetics.org) + BP4, PP3 +BP6 (called benign by Chicago). Notes: May be causal in homozygous state. Susceptibility when homozygous (PMID 15509590), 37 hets and 3 homozygotes in 495 TODAY study -

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

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

.;.;.;.;.;T

Eigen

Benign

-0.034

Eigen_PC

Benign

-0.0048

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.62

T;T;T;T;.;T

MetaRNN

Benign

0.0025

T;T;T;T;T;T

MetaSVM

Benign

-0.60

PhyloP100

3.7

PrimateAI

Benign

0.31

PROVEAN

Benign

1.2

N;.;N;N;N;.

REVEL

Uncertain

0.32

Sift

Benign

0.035

D;.;D;D;D;.

Sift4G

Uncertain

0.021

D;.;.;D;D;D

Polyphen

0.83

P;.;.;.;P;.

Vest4

0.20

MVP

0.96

MPC

0.15

ClinPred

0.036

GERP RS

5.1

gMVP

0.46

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.13

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