2-222201151-C-G

Variant names:

• chr2-222201151-C-G
• rs3731858
• NM_181458.4:c.*257G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181458.4(PAX3):​c.*257G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 1,611,526 control chromosomes in the GnomAD database, including 31,869 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.15 (2231 hom., cov: 32)
  • Exomes 𝑓: 0.20 (29638 hom.)
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.111
• Publications: 22 publications found

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]

PAX3 Gene-Disease associations (from GenCC):

• craniofacial-deafness-hand syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Waardenburg syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.*257G>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.*257G>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22822 AN: 151908 Hom.: 2230 Cov.: 32

Gnomad AFR AF: 0.0399

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.274

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.157

GnomAD2 exomes AF: 0.191 AC: 47808 AN: 250408 AF XY: 0.198

Gnomad AFR exome AF: 0.0357

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.215

Gnomad EAS exome AF: 0.285

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.192

Gnomad OTH exome AF: 0.191

GnomAD4 exome AF: 0.198 AC: 288564 AN: 1459500 Hom.: 29638 Cov.: 32 AF XY: 0.200 AC XY: 145400 AN XY: 726182

African (AFR) AF: 0.0319 AC: 1066 AN: 33456

American (AMR) AF: 0.148 AC: 6597 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.216 AC: 5653 AN: 26116

East Asian (EAS) AF: 0.235 AC: 9321 AN: 39598

South Asian (SAS) AF: 0.273 AC: 23517 AN: 86184

European-Finnish (FIN) AF: 0.164 AC: 8735 AN: 53356

Middle Eastern (MID) AF: 0.224 AC: 1290 AN: 5760

European-Non Finnish (NFE) AF: 0.198 AC: 220065 AN: 1110040

Other (OTH) AF: 0.204 AC: 12320 AN: 60298

GnomAD4 genome AF: 0.150 AC: 22818 AN: 152026 Hom.: 2231 Cov.: 32 AF XY: 0.150 AC XY: 11181 AN XY: 74300

African (AFR) AF: 0.0398 AC: 1650 AN: 41472

American (AMR) AF: 0.152 AC: 2317 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 750 AN: 3462

East Asian (EAS) AF: 0.275 AC: 1419 AN: 5166

South Asian (SAS) AF: 0.273 AC: 1314 AN: 4816

European-Finnish (FIN) AF: 0.151 AC: 1600 AN: 10576

Middle Eastern (MID) AF: 0.235 AC: 69 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13268 AN: 67946

Other (OTH) AF: 0.157 AC: 331 AN: 2110

Alfa AF: 0.129 Hom.: 343

Bravo AF: 0.143

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.3
DANN	Benign	0.55
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3731858; hg19: chr2-223065870; COSMIC: COSV60588606; COSMIC: COSV60588606;