Genetic Variant PAX3:p.Asn47Asn (chr2-222297158-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is . The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_181458.4(PAX3):c.141C>T(p.Asn47Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

PAX3
NM_181458.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.45

Publications

0 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):

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

PAX3 links:

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new If you want to explore the variant's impact on the transcript NM_181458.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.48).

BP7

Synonymous conserved (PhyloP=1.45 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181458.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAX3	NM_181458.4	MANE Select	c.141C>T	p.Asn47Asn	synonymous	Exon 2 of 9	NP_852123.1	P23760-7
PAX3	NM_181459.4		c.141C>T	p.Asn47Asn	synonymous	Exon 2 of 10	NP_852124.1	P23760-8
PAX3	NM_001127366.3		c.141C>T	p.Asn47Asn	synonymous	Exon 2 of 9	NP_001120838.1	P23760-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAX3	ENST00000392070.7	TSL:1 MANE Select	c.141C>T	p.Asn47Asn	synonymous	Exon 2 of 9	ENSP00000375922.3	P23760-7
PAX3	ENST00000409551.7	TSL:1	c.141C>T	p.Asn47Asn	synonymous	Exon 2 of 9	ENSP00000386750.3	P23760-6
PAX3	ENST00000336840.11	TSL:1	c.141C>T	p.Asn47Asn	synonymous	Exon 2 of 9	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453576

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

722536

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33282

American (AMR)

AF:

0.00

AC:

AN:

43478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25958

East Asian (EAS)

AF:

0.00

AC:

AN:

39152

South Asian (SAS)

AF:

0.00

AC:

AN:

85036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52426

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108554

Other (OTH)

AF:

0.00

AC:

AN:

59946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.91

PhyloP100

1.4

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over