rs371715169

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 5P and 4B. PP3_StrongPP5BS2

The ENST00000483494.5(PAX4):n.1374G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,605,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PAX4
ENST00000483494.5 non_coding_transcript_exon

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:2

Conservation

PhyloP100: 0.828

Publications

1 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: Uncertain_significance. The variant received 1 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-127611677-C-T is Pathogenic according to our data. Variant chr7-127611677-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13794.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAdExome4 at 6 Unknown,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.772-1G>A		splice_acceptor_variant, intron_variant	Intron 10 of 11	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.772-1G>A		splice_acceptor_variant, intron_variant	Intron 8 of 9		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 link	c.772-1G>A		splice_acceptor_variant, intron_variant	Intron 10 of 11	5	NM_001366110.1	ENSP00000491782.1

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000247

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000410

AC:

AN:

243764

AF XY:

0.00000754

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000552

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1455580

Hom.:

Cov.:

AF XY:

0.00000552

AC XY:

AN XY:

724248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33292

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110562

Other (OTH)

AF:

0.0000166

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150170

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73206

show subpopulations

African (AFR)

AF:

0.0000247

AC:

AN:

40440

American (AMR)

AF:

0.00

AC:

AN:

15142

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4744

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10262

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67674

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 9

Pathogenic:1

Jul 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Type 2 diabetes mellitus

Uncertain:1

Apr 07, 2025

Medgenome Labs Pvt Ltd

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

PAX4-related disorder

Uncertain:1

Aug 14, 2024

3billion

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. However, loss-of-function (LoF) variants are not yet known to be disease-causing for this gene. In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.64 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported to be associated with PAX4 related disorder (ClinVar ID: VCV000013794 /PMID: 17426099). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.00011

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0

.;.;.;.;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.0

.;.;.;.;.

MetaRNN

Benign

0.0

.;.;.;.;.

MutationAssessor

Benign

0.0

.;.;.;.;.

PhyloP100

0.83

PROVEAN

Benign

0.0

.;.;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;.;.

Vest4

0.0

GERP RS

4.5

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.77

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: -4

DS_AL_spliceai

0.65

Position offset: -1

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