7-127610853-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The ENST00000378740.6(PAX4):c.1046A>G(p.Ter349Trpext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 1,536,282 control chromosomes in the GnomAD database, including 456,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.74 ( 42467 hom., cov: 32)

Exomes 𝑓: 0.77 ( 413618 hom. )

Consequence

PAX4
ENST00000378740.6 stop_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.00600

Publications

18 publications found

Variant links:

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

PAX4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

PM4

Stoplost variant in ENST00000378740.6 Downstream stopcodon found after 348 codons.

BP6

Variant 7-127610853-T-C is Benign according to our data. Variant chr7-127610853-T-C is described in ClinVar as Benign. ClinVar VariationId is 358791.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX4	NM_001366110.1 link	c.*211A>G		3_prime_UTR_variant	Exon 12 of 12	ENST00000639438.3	NP_001353039.1
PAX4	NM_001366111.1 link	c.1046A>G	p.Ter349Trpext*?	stop_lost	Exon 10 of 10		NP_001353040.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX4	ENST00000639438.3 link	c.*211A>G		3_prime_UTR_variant	Exon 12 of 12	5	NM_001366110.1	ENSP00000491782.1		A0A1W2PPX4

Frequencies

GnomAD3 genomes

AF:

0.743

AC:

112892

AN:

152022

Hom.:

42440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.713

Gnomad AMI

AF:

0.797

Gnomad AMR

AF:

0.750

Gnomad ASJ

AF:

0.884

Gnomad EAS

AF:

0.368

Gnomad SAS

AF:

0.741

Gnomad FIN

AF:

0.719

Gnomad MID

AF:

0.854

Gnomad NFE

AF:

0.783

Gnomad OTH

AF:

0.744

GnomAD2 exomes

AF:

0.734

AC:

101797

AN:

138708

AF XY:

0.736

show subpopulations

Gnomad AFR exome

AF:

0.709

Gnomad AMR exome

AF:

0.723

Gnomad ASJ exome

AF:

0.874

Gnomad EAS exome

AF:

0.365

Gnomad FIN exome

AF:

0.732

Gnomad NFE exome

AF:

0.787

Gnomad OTH exome

AF:

0.767

GnomAD4 exome

AF:

0.769

AC:

1064249

AN:

1384142

Hom.:

413618

Cov.:

AF XY:

0.768

AC XY:

524459

AN XY:

683108

show subpopulations

African (AFR)

AF:

0.705

AC:

22254

AN:

31576

American (AMR)

AF:

0.732

AC:

26119

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.878

AC:

22114

AN:

25176

East Asian (EAS)

AF:

0.338

AC:

12078

AN:

35734

South Asian (SAS)

AF:

0.743

AC:

58818

AN:

79204

European-Finnish (FIN)

AF:

0.733

AC:

26004

AN:

35488

Middle Eastern (MID)

AF:

0.825

AC:

4690

AN:

5686

European-Non Finnish (NFE)

AF:

0.787

AC:

847745

AN:

1077690

Other (OTH)

AF:

0.767

AC:

44427

AN:

57888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

12939

25877

38816

51754

64693

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20210

40420

60630

80840

101050

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.743

AC:

112969

AN:

152140

Hom.:

42467

Cov.:

AF XY:

0.736

AC XY:

54772

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.713

AC:

29575

AN:

41494

American (AMR)

AF:

0.750

AC:

11462

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.884

AC:

3067

AN:

3470

East Asian (EAS)

AF:

0.367

AC:

1896

AN:

5162

South Asian (SAS)

AF:

0.740

AC:

3563

AN:

4812

European-Finnish (FIN)

AF:

0.719

AC:

7617

AN:

10592

Middle Eastern (MID)

AF:

0.857

AC:

252

AN:

294

European-Non Finnish (NFE)

AF:

0.783

AC:

53240

AN:

68004

Other (OTH)

AF:

0.743

AC:

1570

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

1479

2959

4438

5918

7397

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.774

Hom.:

106273

Bravo

AF:

0.742

TwinsUK

AF:

0.773

AC:

2866

ALSPAC

AF:

0.784

AC:

3022

ExAC

AF:

0.676

AC:

14835

Asia WGS

AF:

0.582

AC:

2027

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Type 2 diabetes mellitus

Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PAX4-related disorder

Benign:1

Feb 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Maturity onset diabetes mellitus in young

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.85

CADD

Benign

(source)

DANN

Benign

0.65

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.00026

PhyloP100

-0.0060

GERP RS

1.4

Mutation Taster

=197/3

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over