rs327517

Variant names:

• chr7-127613775-T-C
• rs327517
• NM_001366110.1:c.543A>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001366110.1(PAX4):​c.543A>G​(p.Gln181Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,910 control chromosomes in the GnomAD database, including 1,216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (624 hom., cov: 31)
  • Exomes 𝑓: 0.0079 (592 hom.)
• Consequence: PAX4 NM_001366110.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.760

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 7-127613775-T-C is Benign according to our data. Variant chr7-127613775-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 129877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.76 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1	c.543A>G	p.Gln181Gln	synonymous_variant	Exon 7 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1	c.543A>G	p.Gln181Gln	synonymous_variant	Exon 5 of 10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3	c.543A>G	p.Gln181Gln	synonymous_variant	Exon 7 of 12	5	NM_001366110.1	ENSP00000491782.1

Frequencies

GnomAD3 genomes AF: 0.0529 AC: 8041 AN: 151940 Hom.: 619 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0450

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.00560

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0218 AC: 5491 AN: 251454 Hom.: 307 AF XY: 0.0167 AC XY: 2275 AN XY: 135894

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0464

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0368

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00151

Gnomad OTH exome AF: 0.0173

GnomAD4 exome AF: 0.00785 AC: 11478 AN: 1461852 Hom.: 592 Cov.: 33 AF XY: 0.00692 AC XY: 5034 AN XY: 727226

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.0456

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0401

Gnomad4 SAS exome AF: 0.00393

Gnomad4 FIN exome AF: 0.000936

Gnomad4 NFE exome AF: 0.000720

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0530 AC: 8058 AN: 152058 Hom.: 624 Cov.: 31 AF XY: 0.0515 AC XY: 3830 AN XY: 74340

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.0448

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0411

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0422

Alfa AF: 0.0146 Hom.: 179

Bravo AF: 0.0624

Asia WGS AF: 0.0310 AC: 108 AN: 3478

EpiCase AF: 0.00131

EpiControl AF: 0.00190

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Maturity onset diabetes mellitus in young Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.1
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs327517; hg19: chr7-127253829; COSMIC: COSV58387843;