rs202175449

chr2-222294110-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The ENST00000409828.7(PAX3):c.643A>G(p.Ser215Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,611,416 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: PAX3 ENST00000409828.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.178

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004402578).
• BP6: Variant 2-222294110-T-C is Benign according to our data. Variant chr2-222294110-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0016 (244/152364) while in subpopulation AFR AF= 0.00551 (229/41584). AF 95% confidence interval is 0.00492. There are 0 homozygotes in gnomad4. There are 112 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.586+57A>G		intron_variant		ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.586+57A>G		intron_variant		1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00550

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.000478

GnomAD3 exomes AF: 0.000409 AC: 102 AN: 249652 Hom.: 1 AF XY: 0.000341 AC XY: 46 AN XY: 134946

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000168 AC: 245 AN: 1459052 Hom.: 1 Cov.: 36 AF XY: 0.000161 AC XY: 117 AN XY: 725436

Gnomad4 AFR exome AF: 0.00583

Gnomad4 AMR exome AF: 0.000314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000631

Gnomad4 OTH exome AF: 0.000365

GnomAD4 genome AF: 0.00160 AC: 244 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.00150 AC XY: 112 AN XY: 74514

Gnomad4 AFR AF: 0.00551

Gnomad4 AMR AF: 0.000784

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: 0.000473

Alfa AF: 0.000361 Hom.: 1

Bravo AF: 0.00189

ESP6500AA AF: 0.00377 AC: 10

ESP6500EA AF: 0.000217 AC: 1

ExAC AF: 0.000478 AC: 58

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 23, 2015

p.Ser215Gly in exon 4A of PAX3: This variant is not expected to have clinical si gnificance because it has been identified in 0.6% (56/10348) of African chromoso mes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; d bSNP rs202175449). In addition, this amino acid position is not conserved acros s species with most other species (including mammals) having a glycine (Gly) at amino acid position 215. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	6.9
Dann	Benign	0.46
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	0.68	D
MutationTaster	Benign	1.0	N;N;N;N;N;N;N;N
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.22
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.14
MVP		0.24
ClinPred		0.021	T
GERP RS		0.43

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: rs202175449; hg19: chr2-223158829;