rs104893652

chr2-222297158-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_181458.4(PAX3):c.141C>G(p.Asn47Lys) variant causes a missense change involving the alteration of a non-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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N47H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.45

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain 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 chr2-222297160-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2049737.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-222297158-G-C is Pathogenic according to our data. Variant chr2-222297158-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4213.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-222297158-G-C is described in Lovd as [Pathogenic]. Variant chr2-222297158-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.141C>G	p.Asn47Lys	missense_variant	2/9	ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.141C>G	p.Asn47Lys	missense_variant	2/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniofacial-deafness-hand syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 1996

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 21, 2022

Identified in a family with craniofacial-deafness-hand syndrome in published literature (Sommer and Bartholomew, 2003); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8664898, 6859126, 27013732, 14556253) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H;H;H
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0, 0.97, 1.0, 0.98	.;.;D;D;.;D;D;D
Vest4		0.97
MutPred		0.97		Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);Gain of methylation at N47 (P = 0.0213);
MVP		0.95
MPC		2.5
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.96
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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

Other links and lift over

dbSNP: rs104893652; hg19: chr2-223161877;