Genetic Variant PAX3:c.792+88C>G (chr2-222231990-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181458.4(PAX3):c.792+88C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.8 in 1,208,638 control chromosomes in the GnomAD database, including 395,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.77 ( 46463 hom., cov: 32)

Exomes 𝑓: 0.80 ( 348616 hom. )

Consequence

PAX3
NM_181458.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.51

Variant links:

Genes affected

PAX3 (HGNC:8617): (paired box 3) This gene is a member of the paired box (PAX) family of transcription factors. Members of the PAX family typically contain a paired box domain and a paired-type homeodomain. These genes play critical roles during fetal development. Mutations in paired box gene 3 are associated with Waardenburg syndrome, craniofacial-deafness-hand syndrome, and alveolar rhabdomyosarcoma. The translocation t(2;13)(q35;q14), which represents a fusion between PAX3 and the forkhead gene, is a frequent finding in alveolar rhabdomyosarcoma. Alternative splicing results in transcripts encoding isoforms with different C-termini. [provided by RefSeq, Jul 2008]

PAX3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 2-222231990-G-C is Benign according to our data. Variant chr2-222231990-G-C is described in ClinVar as [Benign]. Clinvar id is 1278226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.843 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.792+88C>G		intron_variant	Intron 5 of 8	ENST00000392070.7	NP_852123.1	P23760-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 link	c.792+88C>G		intron_variant	Intron 5 of 8	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.775

AC:

117741

AN:

152016

Hom.:

46449

Cov.:

show subpopulations

Gnomad AFR

AF:

0.710

Gnomad AMI

AF:

0.823

Gnomad AMR

AF:

0.760

Gnomad ASJ

AF:

0.770

Gnomad EAS

AF:

0.370

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.819

Gnomad MID

AF:

0.775

Gnomad NFE

AF:

0.849

Gnomad OTH

AF:

0.775

GnomAD4 exome

AF:

0.804

AC:

849519

AN:

1056504

Hom.:

348616

AF XY:

0.800

AC XY:

434976

AN XY:

544048

show subpopulations

Gnomad4 AFR exome

AF:

0.709

Gnomad4 AMR exome

AF:

0.737

Gnomad4 ASJ exome

AF:

0.776

Gnomad4 EAS exome

AF:

0.311

Gnomad4 SAS exome

AF:

0.662

Gnomad4 FIN exome

AF:

0.826

Gnomad4 NFE exome

AF:

0.851

Gnomad4 OTH exome

AF:

0.792

GnomAD4 genome

AF:

0.774

AC:

117805

AN:

152134

Hom.:

46463

Cov.:

AF XY:

0.768

AC XY:

57095

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.710

Gnomad4 AMR

AF:

0.759

Gnomad4 ASJ

AF:

0.770

Gnomad4 EAS

AF:

0.370

Gnomad4 SAS

AF:

0.649

Gnomad4 FIN

AF:

0.819

Gnomad4 NFE

AF:

0.849

Gnomad4 OTH

AF:

0.775

Alfa

AF:

0.765

Hom.:

2426

Bravo

AF:

0.768

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.067

DANN

Benign

0.35

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over