rs104893651

Positions:

• chr2-222297048-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_181458.4(PAX3):​c.251C>T​(p.Ser84Phe) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.13

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 16 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 2-222297048-G-A is Pathogenic according to our data. Variant chr2-222297048-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-222297048-G-A is described in Lovd as [Pathogenic]. Variant chr2-222297048-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX3	NM_181458.4	c.251C>T	p.Ser84Phe	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.251C>T	p.Ser84Phe	missense_variant	2/9	1	NM_181458.4	ENSP00000375922	A1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 1 Pathogenic:3

Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	Waardenburg syn -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1995	- -
Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	PAX3 c.251C>T, p.S84F alters a residue of PAX3 conserved throughout all sequenced vertebrates. It has been reported multiple times as a pathogenic variant in the Palestinian population (PMID: 7726174). In our cohort, the variant was heterozygous in 16 Palestinian children and adults with features of Waardenburg syndrome from 4 extended kindreds (Abu Rayyan 2020). -

Waardenburg syndrome type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 1995

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 18, 2023

For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PAX3 protein function. ClinVar contains an entry for this variant (Variation ID: 4212). This missense change has been observed in individual(s) with Waardenburg syndrome (PMID: 7726174). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 84 of the PAX3 protein (p.Ser84Phe). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	.;.;.;.;.;D;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	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	0.90	D
PROVEAN	Pathogenic	-5.0	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	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;D;D;D
Vest4		0.96
MutPred		0.96		Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);Gain of methylation at K85 (P = 0.0349);
MVP		1.0
MPC		2.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs104893651; hg19: chr2-223161767;