7-127610566-TGTGTGC-T

Variant names:

• chr7-127610566-TGTGTGC-T
• rs886061966
• NM_001366110.1:c.*492_*497delGCACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001366110.1(PAX4):​c.*492_*497delGCACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00301 in 293,646 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (7 hom., cov: 18)
  • Exomes 𝑓: 0.00056 (0 hom.)
• Consequence: PAX4 NM_001366110.1 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.431
• Publications: 1 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00828 (772/93208) while in subpopulation AFR AF = 0.0312 (720/23084). AF 95% confidence interval is 0.0293. There are 7 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 18. This position passed quality control check.
• BS2: High AC in GnomAd4 at 772 AD,Unknown 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.*492_*497delGCACAC		3_prime_UTR	Exon 12 of 12	NP_001353039.1	A0A1W2PPX4
	PAX4	NM_001366111.1		c.*280_*285delGCACAC		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.*492_*497delGCACAC		3_prime_UTR	Exon 12 of 12	ENSP00000491782.1	A0A1W2PPX4
	PAX4	ENST00000341640.6	TSL:1	c.*492_*497delGCACAC		3_prime_UTR	Exon 9 of 9	ENSP00000339906.2	O43316-4
	PAX4	ENST00000378740.6	TSL:1	c.*280_*285delGCACAC		downstream_gene	N/A	ENSP00000368014.4	J3KPG0

Frequencies

GnomAD3 genomes AF: 0.00825 AC: 768 AN: 93136 Hom.: 7 Cov.: 18

Gnomad AFR AF: 0.0311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00429

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00510

Gnomad NFE AF: 0.0000917

Gnomad OTH AF: 0.00729

GnomAD4 exome AF: 0.000559 AC: 112 AN: 200438 Hom.: 0 AF XY: 0.000462 AC XY: 49 AN XY: 106156

African (AFR) AF: 0.0139 AC: 92 AN: 6622

American (AMR) AF: 0.00117 AC: 9 AN: 7698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5600

East Asian (EAS) AF: 0.000149 AC: 2 AN: 13392

South Asian (SAS) AF: 0.00 AC: 0 AN: 27984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 814

European-Non Finnish (NFE) AF: 0.0000254 AC: 3 AN: 117922

Other (OTH) AF: 0.000542 AC: 6 AN: 11066

GnomAD4 genome AF: 0.00828 AC: 772 AN: 93208 Hom.: 7 Cov.: 18 AF XY: 0.00804 AC XY: 364 AN XY: 45292

African (AFR) AF: 0.0312 AC: 720 AN: 23084

American (AMR) AF: 0.00428 AC: 38 AN: 8876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2094

East Asian (EAS) AF: 0.00 AC: 0 AN: 4554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6356

Middle Eastern (MID) AF: 0.00575 AC: 1 AN: 174

European-Non Finnish (NFE) AF: 0.0000917 AC: 4 AN: 43638

Other (OTH) AF: 0.00718 AC: 9 AN: 1254

Alfa AF: 0.00565 Hom.: 0

Asia WGS AF: 0.00293 AC: 10 AN: 3422

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Maturity-onset diabetes of the young (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs886061966; hg19: chr7-127250620;