rs199651907

chr2-222221309-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_181458.4(PAX3):c.871C>T(p.Pro291Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P291P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.60

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]

LOC107985991 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000103 (15/1461736) while in subpopulation EAS AF= 0.000378 (15/39690). AF 95% confidence interval is 0.000233. There are 0 homozygotes in gnomad4_exome. There are 8 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.871C>T	p.Pro291Ser	missense_variant	6/9	ENST00000392070.7
LOC107985991	XR_001739903.2	n.620G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.871C>T	p.Pro291Ser	missense_variant	6/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

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: 0.0000103 AC: 15 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727162

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74474

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 21, 2016

The p.Pro290Ser variant in PAX3 has not been previously reported in individuals with hearing loss or Waardenburg syndrome or in large population studies. Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro290Ser variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 27, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.0	M;M;M;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.029	D;D;D;D;D;D
Sift4G	Benign	0.11	T;T;T;T;T;T
Polyphen		0.64, 0.99, 0.35	.;.;P;D;.;B
Vest4		0.77
MutPred		0.42		Gain of glycosylation at P291 (P = 0.0096);Gain of glycosylation at P291 (P = 0.0096);Gain of glycosylation at P291 (P = 0.0096);Gain of glycosylation at P291 (P = 0.0096);.;Gain of glycosylation at P291 (P = 0.0096);
MVP		0.86
MPC		0.68
ClinPred		0.96	D
GERP RS		6.1
Varity_R		0.36
gMVP		0.74

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

Other links and lift over

dbSNP: rs199651907; hg19: chr2-223086028;