7-127610874-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000378740.6(PAX4):c.1025C>T(p.Thr342Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000723 in 1,539,682 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00037 (7 hom.)
• Consequence: PAX4 ENST00000378740.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0100

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0049016774).
• BP6: Variant 7-127610874-G-A is Benign according to our data. Variant chr7-127610874-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 358792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 599 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX4	NM_001366110.1	c.*190C>T		3_prime_UTR_variant	12/12	ENST00000639438.3
PAX4	NM_001366111.1	c.1025C>T	p.Thr342Ile	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX4	ENST00000378740.6	c.1025C>T	p.Thr342Ile	missense_variant	10/10	1		P2
PAX4	ENST00000639438.3	c.*190C>T		3_prime_UTR_variant	12/12	5	NM_001366110.1	A2
PAX4	ENST00000341640.6	c.*190C>T		3_prime_UTR_variant	9/9	1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152216 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0139

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00100 AC: 141 AN: 140410 Hom.: 1 AF XY: 0.000697 AC XY: 53 AN XY: 76038

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.000611

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000444

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000179

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.000370 AC: 514 AN: 1387348 Hom.: 7 Cov.: 55 AF XY: 0.000307 AC XY: 210 AN XY: 684600

Gnomad4 AFR exome AF: 0.0138

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000252

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.000656

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152334 Hom.: 4 Cov.: 33 AF XY: 0.00375 AC XY: 279 AN XY: 74494

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00198 Hom.: 0

Bravo AF: 0.00472

ExAC AF: 0.000592 AC: 20

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 31, 2022

- -

PAX4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Maturity onset diabetes mellitus in young Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	2.6
Dann	Benign	0.27
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.36	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.44	N;.
REVEL	Benign	0.096
Sift	Benign	0.092	T;.
Vest4		0.13
MVP		0.19
ClinPred		0.00049	T
GERP RS		-0.095

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: rs2233585; hg19: chr7-127250928;