chr7-127610566-TGTGTGC-T

Position:

• chr7-127610566-TGTGTGC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001366110.1(PAX4):​c.*492_*497del 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

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 Likely_benign. Variant got -5 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 male gnomad4 subpopulation. Median coverage is 18. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 772 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX4	NM_001366110.1	c.*492_*497del		3_prime_UTR_variant	12/12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1	c.*280_*285del		3_prime_UTR_variant	10/10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3	c.*492_*497del		3_prime_UTR_variant	12/12	5	NM_001366110.1	ENSP00000491782	A2
PAX4	ENST00000341640.6	c.*492_*497del		3_prime_UTR_variant	9/9	1		ENSP00000339906

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

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.00117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000149

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000254

Gnomad4 OTH exome AF: 0.000542

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

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00428

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000917

Gnomad4 OTH AF: 0.00718

Alfa AF: 0.00565 Hom.: 0

Asia WGS AF: 0.00293 AC: 10 AN: 3422

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Maturity onset diabetes mellitus in young Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs886061966; hg19: chr7-127250620;