2-222201817-CAAAAAAA-CAAAAAAAAA

Variant names:

• chr2-222201817-C-CAA
• rs368725878
• NM_181458.4:c.1420+125_1420+126dupTT

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_181457.4(PAX3):​c.*105_*106dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00637 in 1,437,694 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 24)
  • Exomes 𝑓: 0.0067 (0 hom.)
• Consequence: PAX3 NM_181457.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.474
• Publications: 3 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: G2P, Orphanet, 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00309 (393/127388) while in subpopulation EAS AF = 0.00709 (32/4516). AF 95% confidence interval is 0.00606. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181457.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	NM_181458.4	MANE Select	c.1420+125_1420+126dupTT		intron	N/A	NP_852123.1	P23760-7
	PAX3	NM_181457.4		c.*105_*106dupTT		3_prime_UTR	Exon 8 of 8	NP_852122.1	P23760-1
	PAX3	NM_181459.4		c.1420+125_1420+126dupTT		intron	N/A	NP_852124.1	P23760-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.1420+125_1420+126dupTT		intron	N/A	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.1417+125_1417+126dupTT		intron	N/A	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.1174-377_1174-376dupTT		intron	N/A	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 392 AN: 127332 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00680

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000649

Gnomad EAS AF: 0.00685

Gnomad SAS AF: 0.00491

Gnomad FIN AF: 0.000903

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00174

GnomAD4 exome AF: 0.00669 AC: 8767 AN: 1310306 Hom.: 0 Cov.: 0 AF XY: 0.00696 AC XY: 4517 AN XY: 649310

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00733 AC: 215 AN: 29334

American (AMR) AF: 0.00475 AC: 160 AN: 33666

Ashkenazi Jewish (ASJ) AF: 0.00967 AC: 222 AN: 22952

East Asian (EAS) AF: 0.00945 AC: 342 AN: 36208

South Asian (SAS) AF: 0.0107 AC: 788 AN: 73814

European-Finnish (FIN) AF: 0.00795 AC: 343 AN: 43120

Middle Eastern (MID) AF: 0.00967 AC: 38 AN: 3928

European-Non Finnish (NFE) AF: 0.00617 AC: 6248 AN: 1012852

Other (OTH) AF: 0.00755 AC: 411 AN: 54432

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00309 AC: 393 AN: 127388 Hom.: 1 Cov.: 24 AF XY: 0.00350 AC XY: 214 AN XY: 61182

African (AFR) AF: 0.00678 AC: 231 AN: 34068

American (AMR) AF: 0.00170 AC: 21 AN: 12344

Ashkenazi Jewish (ASJ) AF: 0.000649 AC: 2 AN: 3084

East Asian (EAS) AF: 0.00709 AC: 32 AN: 4516

South Asian (SAS) AF: 0.00493 AC: 20 AN: 4058

European-Finnish (FIN) AF: 0.000903 AC: 7 AN: 7754

Middle Eastern (MID) AF: 0.00407 AC: 1 AN: 246

European-Non Finnish (NFE) AF: 0.00129 AC: 76 AN: 58808

Other (OTH) AF: 0.00172 AC: 3 AN: 1740

Alfa AF: 0.000145 Hom.: 110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368725878; hg19: chr2-223066536; COSMIC: COSV60590739; COSMIC: COSV60590739;