rs327518

Variant names:

• chr7-127611738-G-A
• rs327518
• ENST00000483494.5:n.1313C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000483494.5(PAX4):​n.1313C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.373 in 1,601,966 control chromosomes in the GnomAD database, including 117,809 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8438 hom., cov: 32)
  • Exomes 𝑓: 0.38 (109371 hom.)
• Consequence: PAX4 ENST00000483494.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.09
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-127611738-G-A is Benign according to our data. Variant chr7-127611738-G-A is described in ClinVar as Benign. ClinVar VariationId is 1292426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.397 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1	c.772-62C>T		intron_variant	Intron 10 of 11	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1	c.772-62C>T		intron_variant	Intron 8 of 9		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3	c.772-62C>T		intron_variant	Intron 10 of 11	5	NM_001366110.1	ENSP00000491782.1

Frequencies

GnomAD3 genomes AF: 0.303 AC: 46075 AN: 151862 Hom.: 8432 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.489

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.401

Gnomad OTH AF: 0.340

GnomAD4 exome AF: 0.381 AC: 551964 AN: 1450006 Hom.: 109371 Cov.: 49 AF XY: 0.379 AC XY: 273315 AN XY: 721532

African (AFR) AF: 0.105 AC: 3525 AN: 33432

American (AMR) AF: 0.442 AC: 19712 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12919 AN: 26120

East Asian (EAS) AF: 0.106 AC: 4198 AN: 39694

South Asian (SAS) AF: 0.301 AC: 25916 AN: 86064

European-Finnish (FIN) AF: 0.292 AC: 12587 AN: 43118

Middle Eastern (MID) AF: 0.430 AC: 2301 AN: 5350

European-Non Finnish (NFE) AF: 0.403 AC: 448231 AN: 1111424

Other (OTH) AF: 0.375 AC: 22575 AN: 60210

GnomAD4 genome AF: 0.303 AC: 46091 AN: 151960 Hom.: 8438 Cov.: 32 AF XY: 0.299 AC XY: 22207 AN XY: 74252

African (AFR) AF: 0.114 AC: 4707 AN: 41454

American (AMR) AF: 0.401 AC: 6122 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.489 AC: 1696 AN: 3470

East Asian (EAS) AF: 0.100 AC: 518 AN: 5164

South Asian (SAS) AF: 0.300 AC: 1439 AN: 4796

European-Finnish (FIN) AF: 0.296 AC: 3114 AN: 10536

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.401 AC: 27260 AN: 67956

Other (OTH) AF: 0.344 AC: 726 AN: 2110

Alfa AF: 0.369 Hom.: 28830

Bravo AF: 0.307

Asia WGS AF: 0.219 AC: 760 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.56
DANN	Benign	0.51
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs327518; hg19: chr7-127251792; COSMIC: COSV58388384; COSMIC: COSV58388384;