2-222298597-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_181458.4(PAX3):​c.19G>T​(p.Ala7Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,606,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

PAX3
NM_181458.4 missense

Scores

2
4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.47
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]
CCDC140 (HGNC:26514): (CCDC140 long non-coding RNA) This gene encodes a protein that appears to be restricted to select higher primate species. This protein contains a C-terminal coiled-coil domain, which is a versatile structural motif consisting of multiple amphipathic alpha-helices that twist around each other to form a supercoil. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12077358).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAX3NM_181458.4 linkc.19G>T p.Ala7Ser missense_variant Exon 1 of 9 ENST00000392070.7 NP_852123.1 P23760-7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PAX3ENST00000392070.7 linkc.19G>T p.Ala7Ser missense_variant Exon 1 of 9 1 NM_181458.4 ENSP00000375922.3 P23760-7

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000175
AC:
4
AN:
229148
Hom.:
0
AF XY:
0.0000159
AC XY:
2
AN XY:
125510
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000391
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000316
AC:
46
AN:
1454458
Hom.:
0
Cov.:
30
AF XY:
0.0000263
AC XY:
19
AN XY:
722894
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000415
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152238
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000564
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000827
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Aug 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with PAX3-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 7 of the PAX3 protein (p.Ala7Ser). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.078
BayesDel_addAF
Uncertain
0.050
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
23
DANN
Benign
0.97
DEOGEN2
Benign
0.21
.;.;.;.;.;T;.;.
Eigen
Benign
-0.54
Eigen_PC
Benign
-0.37
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.90
D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.40
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T
MetaSVM
Pathogenic
0.86
D
MutationAssessor
Benign
-0.34
N;N;N;N;N;N;N;N
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-0.23
N;N;N;N;N;N;N;N
REVEL
Benign
0.29
Sift
Benign
0.15
T;T;T;T;T;T;T;T
Sift4G
Benign
0.52
T;T;T;T;T;T;T;T
Polyphen
0.15, 0.099, 0.092, 0.086, 0.022
.;.;B;B;.;B;B;B
Vest4
0.055
MutPred
0.21
Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);Gain of phosphorylation at A7 (P = 0.0228);
MVP
0.53
MPC
1.3
ClinPred
0.17
T
GERP RS
4.5
Varity_R
0.15
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs778065633; hg19: chr2-223163316; API