ENST00000639438:c.*514_*517dupACAC

Variant names:

• chr7-127610546-A-AGTGT
• rs36159526
• NM_001366110.1:c.*514_*517dupACAC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The ENST00000639438.3(PAX4):​c.*514_*517dupACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0056 (1 hom.)
• Consequence: PAX4 ENST00000639438.3 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 -4 ACMG points.

• BS2: High AC in GnomAd4 at 972 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000639438.3. 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.*514_*517dupACAC		3_prime_UTR	Exon 12 of 12	NP_001353039.1	A0A1W2PPX4
	PAX4	NM_001366111.1		c.*302_*305dupACAC		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.*514_*517dupACAC		3_prime_UTR	Exon 12 of 12	ENSP00000491782.1	A0A1W2PPX4
	PAX4	ENST00000341640.6	TSL:1	c.*514_*517dupACAC		3_prime_UTR	Exon 9 of 9	ENSP00000339906.2	O43316-4

Frequencies

GnomAD3 genomes AF: 0.00679 AC: 966 AN: 142216 Hom.: 2 Cov.: 0

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.00181

Gnomad SAS AF: 0.00820

Gnomad FIN AF: 0.000509

Gnomad MID AF: 0.0130

Gnomad NFE AF: 0.00427

Gnomad OTH AF: 0.00725

GnomAD4 exome AF: 0.00561 AC: 348 AN: 62014 Hom.: 1 Cov.: 0 AF XY: 0.00554 AC XY: 179 AN XY: 32330

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

African (AFR) AF: 0.00802 AC: 21 AN: 2618

American (AMR) AF: 0.00857 AC: 28 AN: 3268

Ashkenazi Jewish (ASJ) AF: 0.0243 AC: 43 AN: 1768

East Asian (EAS) AF: 0.000983 AC: 6 AN: 6104

South Asian (SAS) AF: 0.00857 AC: 41 AN: 4782

European-Finnish (FIN) AF: 0.000743 AC: 2 AN: 2690

Middle Eastern (MID) AF: 0.00699 AC: 2 AN: 286

European-Non Finnish (NFE) AF: 0.00501 AC: 185 AN: 36922

Other (OTH) AF: 0.00559 AC: 20 AN: 3576

⚠️ 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: 0.00683 AC: 972 AN: 142316 Hom.: 3 Cov.: 0 AF XY: 0.00699 AC XY: 485 AN XY: 69400

African (AFR) AF: 0.0122 AC: 442 AN: 36362

American (AMR) AF: 0.00653 AC: 94 AN: 14390

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 88 AN: 3404

East Asian (EAS) AF: 0.00161 AC: 8 AN: 4958

South Asian (SAS) AF: 0.00819 AC: 36 AN: 4396

European-Finnish (FIN) AF: 0.000509 AC: 5 AN: 9822

Middle Eastern (MID) AF: 0.0141 AC: 4 AN: 284

European-Non Finnish (NFE) AF: 0.00425 AC: 280 AN: 65852

Other (OTH) AF: 0.00769 AC: 15 AN: 1950

Alfa AF: 0.00127 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs36159526;

hg19: chr7-127250600;