rs77039439

chr7-127613844-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_001366110.1(PAX4):c.474C>T(p.Gly158=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0588 in 1,613,926 control chromosomes in the GnomAD database, including 3,209 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 0.046 (201 hom., cov: 30)
  • Exomes 𝑓: 0.060 (3008 hom.)
• Consequence: PAX4 NM_001366110.1 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.211

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-127613844-G-A is Benign according to our data. Variant chr7-127613844-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129876.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5, Likely_benign=1}.
• BP7: Synonymous conserved (PhyloP=0.211 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX4	NM_001366110.1	c.474C>T	p.Gly158=	synonymous_variant	7/12	ENST00000639438.3
PAX4	NM_001366111.1	c.474C>T	p.Gly158=	synonymous_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX4	ENST00000639438.3	c.474C>T	p.Gly158=	synonymous_variant	7/12	5	NM_001366110.1	A2

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6927 AN: 152004 Hom.: 201 Cov.: 30

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0298

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0461 AC: 11594 AN: 251452 Hom.: 386 AF XY: 0.0462 AC XY: 6273 AN XY: 135896

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.0245

Gnomad ASJ exome AF: 0.0574

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0129

Gnomad FIN exome AF: 0.0790

Gnomad NFE exome AF: 0.0668

Gnomad OTH exome AF: 0.0458

GnomAD4 exome AF: 0.0602 AC: 88011 AN: 1461804 Hom.: 3008 Cov.: 33 AF XY: 0.0589 AC XY: 42798 AN XY: 727210

Gnomad4 AFR exome AF: 0.00956

Gnomad4 AMR exome AF: 0.0251

Gnomad4 ASJ exome AF: 0.0551

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0133

Gnomad4 FIN exome AF: 0.0758

Gnomad4 NFE exome AF: 0.0688

Gnomad4 OTH exome AF: 0.0543

GnomAD4 genome AF: 0.0455 AC: 6928 AN: 152122 Hom.: 201 Cov.: 30 AF XY: 0.0453 AC XY: 3366 AN XY: 74366

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.0298

Gnomad4 ASJ AF: 0.0582

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0837

Gnomad4 NFE AF: 0.0689

Gnomad4 OTH AF: 0.0398

Alfa AF: 0.0578 Hom.: 145

Bravo AF: 0.0410

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0662

EpiControl AF: 0.0608

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 27, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Maturity onset diabetes mellitus in young Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	research	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	-	This PAX4 gene is associated with MODY, however, no association is found between this particular variant (rs77039439) of PAX4 gene and MODY yet. It needs further validation via clinical studies. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	3.4
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs77039439; hg19: chr7-127253898;