rs114202595

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001366110.1(PAX4):c.385C>T(p.Arg129Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000493 in 1,594,826 control chromosomes in the GnomAD database, including 9 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 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 9 hom. )

Consequence

PAX4
NM_001366110.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 0.0830

Publications

40 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.096687704).

BP6

Variant 7-127614533-G-A is Benign according to our data. Variant chr7-127614533-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13790.

BS2

High AC in GnomAd4 at 38 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.385C>T	p.Arg129Trp	missense_variant	Exon 6 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.385C>T	p.Arg129Trp	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.385C>T	p.Arg129Trp	missense_variant	Exon 6 of 12	5	NM_001366110.1	ENSP00000491782.1		A0A1W2PPX4

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00540

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000119

AC:

AN:

218760

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.0000532

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.000181

GnomAD4 exome

AF:

0.000519

AC:

749

AN:

1442590

Hom.:

Cov.:

AF XY:

0.000520

AC XY:

372

AN XY:

715416

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33220

American (AMR)

AF:

0.0000237

AC:

AN:

42114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25682

East Asian (EAS)

AF:

0.0159

AC:

620

AN:

39024

South Asian (SAS)

AF:

0.00

AC:

AN:

82718

European-Finnish (FIN)

AF:

0.0000574

AC:

AN:

52304

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5558

European-Non Finnish (NFE)

AF:

0.0000998

AC:

110

AN:

1102258

Other (OTH)

AF:

0.000218

AC:

AN:

59712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

110

147

184

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:

0.000250

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41536

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00542

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000497

Hom.:

Bravo

AF:

0.000132

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000149

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus

Pathogenic:1

Dec 01, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not specified

Uncertain:1

May 04, 2022

Mendelics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Jun 27, 2022

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 tryptophan, which is neutral and slightly polar, at codon 121 of the PAX4 protein (p.Arg121Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of type 1 or type 2 diabetes as well as in non-diabetic controls (PMID: 11723072, 16423628, 31264968, 33031055). ClinVar contains an entry for this variant (Variation ID: 13790). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects PAX4 function (PMID: 15596543, 27334367). 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. -

Maturity onset diabetes mellitus in young

Benign:1

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

This PAX4 gene is associated with MODY. This particular variant (rs114202595) seems to be associated with Type II Diabetes Mellitus as well. However, more evidence is required for further validation of this variants impact via clinical studies. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Benign

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

.;.;.;.;.;D

Eigen

Uncertain

0.30

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.16

LIST_S2

Pathogenic

0.98

D;D;D;D;.;D

M_CAP

Pathogenic

0.50

MetaRNN

Benign

0.097

T;T;T;T;T;T

MetaSVM

Pathogenic

0.89

PhyloP100

0.083

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.9

D;.;D;D;D;.

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

D;.;D;D;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;D;D

Polyphen

1.0

D;.;.;.;D;.

Vest4

0.42

MVP

0.97

MPC

0.34

ClinPred

0.57

GERP RS

2.5

gMVP

0.72

Mutation Taster

=7/93

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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