rs35155575

Positions:

• chr7-127615412-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP3 BP4_Strong BP6 BS2

The NM_001366110.1(PAX4):​c.133C>T​(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000269 in 1,614,168 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (3 hom.)
• Consequence: PAX4 NM_001366110.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:1
• Conservation: PhyloP100: 2.61

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.056519568).
• BP6: Variant 7-127615412-G-A is Benign according to our data. Variant chr7-127615412-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 13792.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2, Benign=1}.
• BS2: High AC in GnomAd4 at 209 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX4	NM_001366110.1	c.133C>T	p.Arg45Trp	missense_variant	4/12	ENST00000639438.3
PAX4	NM_001366111.1	c.133C>T	p.Arg45Trp	missense_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX4	ENST00000639438.3	c.133C>T	p.Arg45Trp	missense_variant	4/12	5	NM_001366110.1	A2

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 206 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000427 AC: 107 AN: 250682 Hom.: 1 AF XY: 0.000302 AC XY: 41 AN XY: 135572

Gnomad AFR exome AF: 0.00572

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000155 AC: 226 AN: 1461866 Hom.: 3 Cov.: 69 AF XY: 0.000142 AC XY: 103 AN XY: 727232

Gnomad4 AFR exome AF: 0.00538

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00137 AC: 209 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00124 AC XY: 92 AN XY: 74486

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.00149

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000486 AC: 59

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, flagged submission	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Dec 17, 2019	The p.Arg37Trp variant is predicted to substitute the arginine at position 37 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2021	Published functional studies suggest a damaging effect, specifically in vitro analyses illustrate a reduction in the PAX4-binding ability to target gene promoters (Mauvais-Jarvis et al., 2004); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32801813, 15509590, 20981092) -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 31, 2018	- -

Type 2 diabetes mellitus;C2677132:Maturity-onset diabetes of the young type 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Dec 02, 2021

The heterozygous missense variant c.133C>T (p.Arg45Trp) identified in exon 4 (of 12) of the PAX4 gene has been reported in a patient with Ketosis-prone diabetes (KPD), a rare form of type 2 diabetes, mostly observed in subjects of west Africans and African-Americans (PMID: 15509590). The variant has 0.004851 allele frequency in the African/African American subpopulation represented in the gnomAD(v3.1.2) database (201 heterozygous alleles. Additionally, one homozygous allele in the gnomADv2.1.1 database). This variant is reported as a Variant of Uncertain Significance and benign in the ClinVar database (Variation ID:13792). The variant affects a conserved residue (Arg45) located in the paired box domain of PAX4 gene (PMID: 15509590) and is predicted deleterious by multiple insilico prediction tools (CADD score = 27.9, REVEL score = 0.917). In vitro functional analyses of c.133C>T (p.Arg45Trp) suggested impaired PAX4-binding ability to target gene promoters (PMID: 15509590). Based on the available evidence, the c.133C>T (p.Arg45Trp) variant identified in the PAX4 gene is reported as a Variant of Uncertain Significance. -

Hyperglycemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

-

The p.Arg45Trp variant is predicted to substitute the arginine at position 45 with a tryptophan and the majority of in silico tools predict this variant has a damaging effect. This variant was reported as a heterozygous change in a single individual with ketosis-prone diabetes and was demonstrated to have reduced function in in vitro assays (PMID: 15509590). This variant is found in individuals with African ancestry with an allele frequency of 0.5% (~1/100 are carriers; 1 individual with homozygous change) in the Genome Aggregation Database. -

Diabetes mellitus, ketosis-prone, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Dec 15, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	32
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.057	T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-7.1	D;.;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;.;D;D
Sift4G	Pathogenic	0.0	D;.;.;D
Polyphen		1.0	D;.;.;.
Vest4		0.89
MVP		1.0
MPC		0.34
ClinPred		0.15	T
GERP RS		4.8
gMVP		0.54

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

Other links and lift over

dbSNP: rs35155575; hg19: chr7-127255466; COSMIC: COSV58389351; COSMIC: COSV58389351;