Genetic Variant PAX3:c.1174-8359G>A (chr2-222210549-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181458.4(PAX3):c.1174-8359G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.301 in 152,056 control chromosomes in the GnomAD database, including 8,682 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.30 ( 8682 hom., cov: 32)

Consequence

PAX3
NM_181458.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.255

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

craniofacial-deafness-hand syndrome
Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
Waardenburg syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Waardenburg syndrome type 1
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
Waardenburg syndrome type 3
Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

PAX3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.1174-8359G>A		intron_variant	Intron 7 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.1174-8359G>A		intron_variant	Intron 7 of 8	1	NM_181458.4	ENSP00000375922.3		P23760-7

Frequencies

GnomAD3 genomes

AF:

0.301

AC:

45707

AN:

151938

Hom.:

8684

Cov.:

show subpopulations

Gnomad AFR

AF:

0.108

Gnomad AMI

AF:

0.652

Gnomad AMR

AF:

0.227

Gnomad ASJ

AF:

0.318

Gnomad EAS

AF:

0.0901

Gnomad SAS

AF:

0.199

Gnomad FIN

AF:

0.475

Gnomad MID

AF:

0.334

Gnomad NFE

AF:

0.426

Gnomad OTH

AF:

0.296

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.301

AC:

45705

AN:

152056

Hom.:

8682

Cov.:

AF XY:

0.297

AC XY:

22036

AN XY:

74292

show subpopulations

African (AFR)

AF:

0.107

AC:

4462

AN:

41518

American (AMR)

AF:

0.226

AC:

3460

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

1102

AN:

3468

East Asian (EAS)

AF:

0.0897

AC:

464

AN:

5170

South Asian (SAS)

AF:

0.199

AC:

956

AN:

4814

European-Finnish (FIN)

AF:

0.475

AC:

5000

AN:

10532

Middle Eastern (MID)

AF:

0.346

AC:

101

AN:

292

European-Non Finnish (NFE)

AF:

0.426

AC:

28939

AN:

67960

Other (OTH)

AF:

0.297

AC:

626

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1512

3024

4536

6048

7560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.251

Hom.:

708

Bravo

AF:

0.276

Asia WGS

AF:

0.156

AC:

544

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.8

(source)

DANN

Benign

0.67

PhyloP100

-0.26

Mutation Taster

=100/0

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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2-222210549-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over