7-127610546-AGT-A

Variant names:

• chr7-127610546-AGT-A
• rs36159526
• NM_001366110.1:c.*516_*517delAC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001366110.1(PAX4):​c.*516_*517delAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 200,804 control chromosomes in the GnomAD database, including 17 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (15 hom., cov: 0)
  • Exomes 𝑓: 0.063 (2 hom.)
• Consequence: PAX4 NM_001366110.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.286
• Publications: 2 publications found

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]

PAX4 Gene-Disease associations (from GenCC):

• maturity-onset diabetes of the young

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• diabetes mellitus, noninsulin-dependent

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• maturity-onset diabetes of the young type 9

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• monogenic diabetes

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0078 (1109/142162) while in subpopulation AFR AF = 0.0259 (941/36360). AF 95% confidence interval is 0.0245. There are 15 homozygotes in GnomAd4. There are 535 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 1109 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366110.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	NM_001366110.1	MANE Select	c.*516_*517delAC		3_prime_UTR	Exon 12 of 12	NP_001353039.1	A0A1W2PPX4
	PAX4	NM_001366111.1		c.*304_*305delAC		3_prime_UTR	Exon 10 of 10	NP_001353040.1	J3KPG0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX4	ENST00000639438.3	TSL:5 MANE Select	c.*516_*517delAC		3_prime_UTR	Exon 12 of 12	ENSP00000491782.1	A0A1W2PPX4
	PAX4	ENST00000341640.6	TSL:1	c.*516_*517delAC		3_prime_UTR	Exon 9 of 9	ENSP00000339906.2	O43316-4

Frequencies

GnomAD3 genomes AF: 0.00776 AC: 1102 AN: 142062 Hom.: 15 Cov.: 0

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.000588

Gnomad EAS AF: 0.000201

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.000614

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00673

GnomAD4 exome AF: 0.0630 AC: 3692 AN: 58642 Hom.: 2 AF XY: 0.0632 AC XY: 1933 AN XY: 30568

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0616 AC: 155 AN: 2518

American (AMR) AF: 0.0520 AC: 161 AN: 3096

Ashkenazi Jewish (ASJ) AF: 0.0518 AC: 87 AN: 1678

East Asian (EAS) AF: 0.107 AC: 598 AN: 5578

South Asian (SAS) AF: 0.0655 AC: 294 AN: 4488

European-Finnish (FIN) AF: 0.0651 AC: 167 AN: 2564

Middle Eastern (MID) AF: 0.0683 AC: 19 AN: 278

European-Non Finnish (NFE) AF: 0.0567 AC: 1987 AN: 35032

Other (OTH) AF: 0.0657 AC: 224 AN: 3410

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00780 AC: 1109 AN: 142162 Hom.: 15 Cov.: 0 AF XY: 0.00772 AC XY: 535 AN XY: 69302

African (AFR) AF: 0.0259 AC: 941 AN: 36360

American (AMR) AF: 0.00320 AC: 46 AN: 14370

Ashkenazi Jewish (ASJ) AF: 0.000588 AC: 2 AN: 3404

East Asian (EAS) AF: 0.000202 AC: 1 AN: 4950

South Asian (SAS) AF: 0.00410 AC: 18 AN: 4394

European-Finnish (FIN) AF: 0.000614 AC: 6 AN: 9768

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00125 AC: 82 AN: 65786

Other (OTH) AF: 0.00667 AC: 13 AN: 1950

Alfa AF: 0.00174 Hom.: 301

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Maturity-onset diabetes of the young (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs36159526; hg19: chr7-127250600;