rs28945092

Positions:

• chr2-222297143-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_181458.4(PAX3):​c.156C>G​(p.Pro52=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00236 in 1,608,192 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0097 (24 hom., cov: 34)
  • Exomes 𝑓: 0.0016 (28 hom.)
• Consequence: PAX3 NM_181458.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.42

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-222297143-G-C is Benign according to our data. Variant chr2-222297143-G-C is described in ClinVar as [Benign]. Clinvar id is 226994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-222297143-G-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=3.42 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00966 (1472/152376) while in subpopulation AFR AF= 0.0313 (1300/41592). AF 95% confidence interval is 0.0298. There are 24 homozygotes in gnomad4. There are 722 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 24 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.156C>G	p.Pro52=	synonymous_variant	2/9	ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.156C>G	p.Pro52=	synonymous_variant	2/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes AF: 0.00965 AC: 1469 AN: 152258 Hom.: 24 Cov.: 34

Gnomad AFR AF: 0.0313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00868

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00332 AC: 779 AN: 234596 Hom.: 5 AF XY: 0.00283 AC XY: 362 AN XY: 128042

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.00291

Gnomad ASJ exome AF: 0.000822

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.00555

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000496

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00159 AC: 2320 AN: 1455816 Hom.: 28 Cov.: 33 AF XY: 0.00160 AC XY: 1160 AN XY: 723910

Gnomad4 AFR exome AF: 0.0289

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.000538

Gnomad4 EAS exome AF: 0.0000509

Gnomad4 SAS exome AF: 0.00609

Gnomad4 FIN exome AF: 0.0000192

Gnomad4 NFE exome AF: 0.000434

Gnomad4 OTH exome AF: 0.00282

GnomAD4 genome AF: 0.00966 AC: 1472 AN: 152376 Hom.: 24 Cov.: 34 AF XY: 0.00969 AC XY: 722 AN XY: 74520

Gnomad4 AFR AF: 0.0313

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00321 Hom.: 1

Bravo AF: 0.0107

Asia WGS AF: 0.00982 AC: 34 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro52Pro in exon 2 of PAX3: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 2.6% (114/4396) of Afr ican American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs28945092). -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	- -

Craniofacial-deafness-hand syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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	-0.53
CADD	Benign	14
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs28945092; hg19: chr2-223161862;