2-222201414-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The ENST00000336840.11(PAX3):c.1202C>T(p.Ser401Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,744 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/15 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PAX3 ENST00000336840.11 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.951

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017596334).
• BP6: Variant 2-222201414-G-A is Benign according to our data. Variant chr2-222201414-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 227834.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000132 (20/151944) while in subpopulation EAS AF= 0.00155 (8/5162). AF 95% confidence interval is 0.000771. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.1449C>T	p.Ile483=	synonymous_variant	9/9	ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.1449C>T	p.Ile483=	synonymous_variant	9/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151944 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000140 AC: 35 AN: 250390 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135396

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000708

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461800 Hom.: 2 Cov.: 34 AF XY: 0.000164 AC XY: 119 AN XY: 727200

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00139

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151944 Hom.: 0 Cov.: 31 AF XY: 0.0000943 AC XY: 7 AN XY: 74206

Gnomad4 AFR AF: 0.0000726

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000958

Alfa AF: 0.000355 Hom.: 1

Bravo AF: 0.000200

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 21, 2016

c.1202C>T (p.Ser401Leu) in exon 8E of PAX3: This variant is not expected to hav e clinical significance. It is located in an alternate transcript (NM_181461.3) in which the variant nucleotide (T) is present in over 10 mammals, despite high conservation at the adjacent nucleotides. This variant is also translated to a silent variant in the major transcript (NM_001127366.2, c.1446C>T, p.Ile482Ile) , and it is in noncoding regions of other alternate transcripts (NM_000438.5, NM _013942.4, NM_181457.3). This variant has been identified in 0.1% (9/8612) of E ast Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org). In summary, this variant is likely benign due to the lack of nucleotide conservation and predicted impact on the gene function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Benign	9.0
Dann	Benign	0.90
Eigen	Benign	0.12
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.33	T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Uncertain	0.070	D
MutationTaster	Benign	1.0	D;D;D;D;N;N
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.12	T;D
Sift4G	Benign	0.092	T;D
Polyphen		0.0	B;B
Vest4		0.29
MutPred		0.37		Gain of catalytic residue at S401 (P = 0.011);Gain of catalytic residue at S401 (P = 0.011);
MVP		0.55
ClinPred		0.045	T
GERP RS		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs757964568; hg19: chr2-223066133;