rs712701

Positions:

• chr7-127611134-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.26

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 -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: {Benign=6, Uncertain_significance=1}. 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	UniProt
PAX4	NM_001366110.1	c.986A>C	p.His329Pro	missense_variant	12/12	ENST00000639438.3
PAX4	NM_001366111.1	c.914-149A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX4	ENST00000639438.3	c.986A>C	p.His329Pro	missense_variant	12/12	5	NM_001366110.1	A2

Frequencies

GnomAD3 genomes AF: 0.744 AC: 113033 AN: 152018 Hom.: 42543 Cov.: 33

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

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.: 65 AF XY: 0.767 AC XY: 553258 AN XY: 721650

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.: 33 AF XY: 0.738 AC XY: 54840 AN XY: 74358

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:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Maturity onset diabetes mellitus in young Uncertain:1 Benign: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	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 15509590, 20360641, 15834548, 27334367) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

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	T
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	N
LIST_S2	Benign	0.18	T;T;.
MetaRNN	Benign	0.0000012	T;T;T
MetaSVM	Benign	-0.97	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.27	T
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	T
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

Other links and lift over

dbSNP: rs712701; hg19: chr7-127251188; COSMIC: COSV58387831; COSMIC: COSV58387831;