2-222201034-TACACACACAC-TACACACAC

Variant names:

• chr2-222201034-TAC-T
• rs373626774
• NM_181458.4:c.*372_*373delGT

Variant summary

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

The NM_181458.4(PAX3):​c.*372_*373delGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0686 in 579,182 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.092 (0 hom.)
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.847
• Publications: 4 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: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00143 (213/148860) while in subpopulation AFR AF = 0.00421 (172/40900). AF 95% confidence interval is 0.00369. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.*372_*373delGT		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.*372_*373delGT		3_prime_UTR_variant	Exon 9 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.00144 AC: 214 AN: 148766 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00424

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000470

Gnomad ASJ AF: 0.000293

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.000411

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000374

Gnomad OTH AF: 0.000489

GnomAD4 exome AF: 0.0919 AC: 39539 AN: 430322 Hom.: 0 AF XY: 0.0938 AC XY: 20667 AN XY: 220446

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

African (AFR) AF: 0.0622 AC: 758 AN: 12184

American (AMR) AF: 0.108 AC: 1962 AN: 18114

Ashkenazi Jewish (ASJ) AF: 0.103 AC: 1022 AN: 9914

East Asian (EAS) AF: 0.105 AC: 1501 AN: 14238

South Asian (SAS) AF: 0.111 AC: 3033 AN: 27290

European-Finnish (FIN) AF: 0.0982 AC: 2568 AN: 26162

Middle Eastern (MID) AF: 0.0471 AC: 140 AN: 2974

European-Non Finnish (NFE) AF: 0.0892 AC: 26699 AN: 299364

Other (OTH) AF: 0.0924 AC: 1856 AN: 20082

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00143 AC: 213 AN: 148860 Hom.: 0 Cov.: 31 AF XY: 0.00141 AC XY: 102 AN XY: 72550

African (AFR) AF: 0.00421 AC: 172 AN: 40900

American (AMR) AF: 0.000469 AC: 7 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.000293 AC: 1 AN: 3410

East Asian (EAS) AF: 0.000393 AC: 2 AN: 5088

South Asian (SAS) AF: 0.000214 AC: 1 AN: 4674

European-Finnish (FIN) AF: 0.000411 AC: 4 AN: 9734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000374 AC: 25 AN: 66866

Other (OTH) AF: 0.000484 AC: 1 AN: 2064

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.85
Mutation Taster		=100/0	polymorphism

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: rs373626774; hg19: chr2-223065753; COSMIC: COSV60585862; COSMIC: COSV60585862;