rs712701

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_001366110.1(PAX4):c.986A>C(p.His329Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 1,604,714 control chromosomes in the GnomAD database, including 474,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.74 ( 42570 hom., cov: 33)

Exomes 𝑓: 0.77 ( 432365 hom. )

Consequence

PAX4
NM_001366110.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -1.26

Publications

55 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.1978148E-6).

BP6

Variant 7-127611134-T-G is Benign according to our data. Variant chr7-127611134-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129878.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.986A>C	p.His329Pro	missense_variant	Exon 12 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.914-149A>C		intron_variant	Intron 9 of 9		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 link	c.986A>C	p.His329Pro	missense_variant	Exon 12 of 12	5	NM_001366110.1	ENSP00000491782.1		A0A1W2PPX4

Frequencies

GnomAD3 genomes

AF:

0.744

AC:

113033

AN:

152018

Hom.:

42543

Cov.:

show subpopulations

Gnomad AFR

AF:

0.715

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.750

Gnomad ASJ

AF:

0.884

Gnomad EAS

AF:

0.369

Gnomad SAS

AF:

0.742

Gnomad FIN

AF:

0.720

Gnomad MID

AF:

0.858

Gnomad NFE

AF:

0.783

Gnomad OTH

AF:

0.745

GnomAD2 exomes

AF:

0.735

AC:

173183

AN:

235698

AF XY:

0.739

show subpopulations

Gnomad AFR exome

AF:

0.716

Gnomad AMR exome

AF:

0.720

Gnomad ASJ exome

AF:

0.877

Gnomad EAS exome

AF:

0.369

Gnomad FIN exome

AF:

0.730

Gnomad NFE exome

AF:

0.787

Gnomad OTH exome

AF:

0.767

GnomAD4 exome

AF:

0.767

AC:

1114723

AN:

1452578

Hom.:

432365

Cov.:

AF XY:

0.767

AC XY:

553258

AN XY:

721650

show subpopulations

African (AFR)

AF:

0.707

AC:

23607

AN:

33370

American (AMR)

AF:

0.728

AC:

31657

AN:

43464

Ashkenazi Jewish (ASJ)

AF:

0.879

AC:

22764

AN:

25908

East Asian (EAS)

AF:

0.341

AC:

13474

AN:

39482

South Asian (SAS)

AF:

0.743

AC:

62823

AN:

84564

European-Finnish (FIN)

AF:

0.731

AC:

38638

AN:

52856

Middle Eastern (MID)

AF:

0.826

AC:

4663

AN:

5646

European-Non Finnish (NFE)

AF:

0.787

AC:

871059

AN:

1107268

Other (OTH)

AF:

0.767

AC:

46038

AN:

60020

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

16396

32792

49189

65585

81981

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20530

41060

61590

82120

102650

<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:

0.743

AC:

113111

AN:

152136

Hom.:

42570

Cov.:

AF XY:

0.738

AC XY:

54840

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.715

AC:

29666

AN:

41504

American (AMR)

AF:

0.750

AC:

11477

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.884

AC:

3069

AN:

3472

East Asian (EAS)

AF:

0.368

AC:

1896

AN:

5146

South Asian (SAS)

AF:

0.741

AC:

3575

AN:

4826

European-Finnish (FIN)

AF:

0.720

AC:

7625

AN:

10590

Middle Eastern (MID)

AF:

0.861

AC:

253

AN:

294

European-Non Finnish (NFE)

AF:

0.783

AC:

53255

AN:

67984

Other (OTH)

AF:

0.743

AC:

1568

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

1509

3018

4526

6035

7544

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

844

1688

2532

3376

4220

<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:

0.756

Hom.:

123517

Bravo

AF:

0.743

TwinsUK

AF:

0.774

AC:

2871

ALSPAC

AF:

0.784

AC:

3020

ESP6500AA

AF:

0.709

AC:

3124

ESP6500EA

AF:

0.800

AC:

6875

ExAC

AF:

0.728

AC:

88168

Asia WGS

AF:

0.583

AC:

2028

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Maturity onset diabetes mellitus in young

Uncertain:1Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Though PAX4 gene is associated with MODY, no sufficeint evidence is found to ascertain the role of this particular variant rs712701 in MODY yet. More clinical studies are required to validate the association. -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Dec 27, 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

- -

not provided

Benign:2

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: 15509590, 20360641, 15834548, 27334367) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Type 2 diabetes mellitus

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

0.60

(source)

DANN

Benign

0.11

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00036

LIST_S2

Benign

0.18

T;T;.

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-0.97

PhyloP100

-1.3

PrimateAI

Benign

0.27

PROVEAN

Benign

1.4

N;.;N

REVEL

Benign

0.16

Sift

Benign

0.41

T;.;T

Sift4G

Benign

0.22

T;.;T

Polyphen

0.0

B;.;B

Vest4

0.081

MPC

0.070

ClinPred

0.0013

GERP RS

-3.4

gMVP

0.12

Mutation Taster

=99/1

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