rs712701

Positions:

chr7-127611134-T-G

Variant summary

Our verdict is Benign. Variant got -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. 13/17 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

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 links:

PAX4 (HGNC:):

PAX4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 129878.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=6}. Variant chr7-127611134-T-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
PAX4	NM_001366110.1 linkuse as main transcript	c.986A>C	p.His329Pro	missense_variant	12/12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 linkuse as main transcript	c.914-149A>C		intron_variant			NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 linkuse as main transcript	c.986A>C	p.His329Pro	missense_variant	12/12	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

GnomAD3 exomes

AF:

0.735

AC:

173183

AN:

235698

Hom.:

64830

AF XY:

0.739

AC XY:

94211

AN XY:

127402

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 SAS exome

AF:

0.742

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

Gnomad4 AFR exome

AF:

0.707

Gnomad4 AMR exome

AF:

0.728

Gnomad4 ASJ exome

AF:

0.879

Gnomad4 EAS exome

AF:

0.341

Gnomad4 SAS exome

AF:

0.743

Gnomad4 FIN exome

AF:

0.731

Gnomad4 NFE exome

AF:

0.787

Gnomad4 OTH exome

AF:

0.767

GnomAD4 genome

AF:

0.743

AC:

113111

AN:

152136

Hom.:

42570

Cov.:

AF XY:

0.738

AC XY:

54840

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.715

Gnomad4 AMR

AF:

0.750

Gnomad4 ASJ

AF:

0.884

Gnomad4 EAS

AF:

0.368

Gnomad4 SAS

AF:

0.741

Gnomad4 FIN

AF:

0.720

Gnomad4 NFE

AF:

0.783

Gnomad4 OTH

AF:

0.743

Alfa

AF:

0.754

Hom.:

87904

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

Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 27, 2013	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 15509590, 20360641, 15834548, 27334367) -

Type 2 diabetes mellitus

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over