rs104893653

Positions:

• chr2-222297160-T-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_181458.4(PAX3):​c.139A>C​(p.Asn47His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47K) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.97

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a DNA_binding_region Paired (size 127) in uniprot entity PAX3_HUMAN there are 53 pathogenic changes around while only 0 benign (100%) in NM_181458.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-222297158-G-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-222297160-T-G is Pathogenic according to our data. Variant chr2-222297160-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 4214.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-222297160-T-G is described in Lovd as [Pathogenic]. Variant chr2-222297160-T-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX3	NM_181458.4	c.139A>C	p.Asn47His	missense_variant	2/9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.139A>C	p.Asn47His	missense_variant	2/9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Waardenburg syndrome type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 1993

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;.;D;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H;H;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99, 0.99	.;.;D;D;.;D;D;D
Vest4		0.99
MutPred		0.96		Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);Gain of catalytic residue at N47 (P = 0.0823);
MVP		0.96
MPC		2.6
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -8

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

Publications

LitVar

Other links and lift over

dbSNP: rs104893653; hg19: chr2-223161879;