rs45501095

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS1

The NM_181458.4(PAX3):​c.-359G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000235 in 446,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PAX3
NM_181458.4 5_prime_UTR

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.804
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 Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 2-222298974-C-A is Benign according to our data. Variant chr2-222298974-C-A is described in ClinVar as [Benign]. Clinvar id is 334567.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000249 (38/152334) while in subpopulation EAS AF= 0.00599 (31/5172). AF 95% confidence interval is 0.00434. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PAX3NM_181458.4 linkc.-359G>T 5_prime_UTR_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.-359G>T 5_prime_UTR_variant Exon 1 of 9 1 NM_181458.4 ENSP00000375922.3 P23760-7

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152216
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00617
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.000228
AC:
67
AN:
294128
Hom.:
0
Cov.:
0
AF XY:
0.000190
AC XY:
29
AN XY:
152450
show subpopulations
Gnomad4 AFR exome
AF:
0.000103
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00244
Gnomad4 SAS exome
AF:
0.0000273
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000967
GnomAD4 genome
AF:
0.000249
AC:
38
AN:
152334
Hom.:
0
Cov.:
33
AF XY:
0.000322
AC XY:
24
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00599
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000153
Hom.:
0
Bravo
AF:
0.000355

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Craniofacial-deafness-hand syndrome Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Waardenburg syndrome Benign:1
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.32
CADD
Benign
17
DANN
Benign
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs45501095; hg19: chr2-223163693; API