2-222297157-C-A

Position:

• chr2-222297157-C-A

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.142G>T​(p.Gly48Cys) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G48D) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 35)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 7.90

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 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 chr2-222297156-C-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-222297157-C-A is Pathogenic according to our data. Variant chr2-222297157-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 488032.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr2-222297157-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX3	NM_181458.4	c.142G>T	p.Gly48Cys	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.142G>T	p.Gly48Cys	missense_variant	2/9	1	NM_181458.4	ENSP00000375922	A1

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 35

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Waardenburg syndrome type 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

Mar 01, 2017

- -

Waardenburg syndrome type 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

research

UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill

Dec 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	.;.;.;.;.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.0	H;H;H;H;H;H;H;H
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;D;D;D
Vest4		0.95
MutPred		0.96		Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);Loss of MoRF binding (P = 0.0797);
MVP		1.0
MPC		2.7
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs1419548558; hg19: chr2-223161876;