rs104893651

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_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. 13/22 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

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.13

Publications

8 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):

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

PAX3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_181458.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 1.618 (below the threshold of 3.09). Trascript score misZ: 1.7934 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 3, Waardenburg syndrome type 1, Waardenburg syndrome, craniofacial-deafness-hand syndrome.

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 VariationId is 4212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4 link	c.251C>T	p.Ser84Phe	missense_variant	Exon 2 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 link	c.251C>T	p.Ser84Phe	missense_variant	Exon 2 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Waardenburg syndrome type 1

Pathogenic:3

Aug 01, 2020

King Laboratory, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

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). -

May 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jun 04, 2016

Hereditary Research Laboratory, Bethlehem University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

Waardenburg syn -

Waardenburg syndrome type 3

Pathogenic:1

May 01, 1995

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

not provided

Pathogenic:1

Jul 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

.;.;.;.;.;D;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.94

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Pathogenic

4.0

H;H;H;H;H;H;H;H

PhyloP100

8.1

PrimateAI

Pathogenic

0.90

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

GERP RS

5.2

Varity_R

0.98

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over