2-222201298-A-ACC

Variant names:

• chr2-222201298-A-ACC
• rs3832105
• NM_181458.4:c.*108_*109dupGG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_181458.4(PAX3):​c.*108_*109dupGG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0045 in 1,446,462 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (20 hom., cov: 29)
  • Exomes 𝑓: 0.0045 (8 hom.)
  • Failed GnomAD Quality Control
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• Publications: 1 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 -6 ACMG points.

• BP6: Variant 2-222201298-A-ACC is Benign according to our data. Variant chr2-222201298-A-ACC is described in ClinVar as [Likely_benign]. Clinvar id is 1186210.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.*108_*109dupGG		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.*108_*109dupGG		3_prime_UTR_variant	Exon 9 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2123 AN: 147936 Hom.: 20 Cov.: 29

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00716

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.00409

Gnomad FIN AF: 0.0000992

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00336

Gnomad OTH AF: 0.00937

GnomAD4 exome AF: 0.00450 AC: 6506 AN: 1446462 Hom.: 8 Cov.: 34 AF XY: 0.00434 AC XY: 3121 AN XY: 719734

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

African (AFR) AF: 0.0368 AC: 1186 AN: 32272

American (AMR) AF: 0.00329 AC: 145 AN: 44056

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 25988

East Asian (EAS) AF: 0.0250 AC: 882 AN: 35330

South Asian (SAS) AF: 0.00377 AC: 321 AN: 85194

European-Finnish (FIN) AF: 0.000189 AC: 10 AN: 52808

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5742

European-Non Finnish (NFE) AF: 0.00330 AC: 3650 AN: 1105394

Other (OTH) AF: 0.00491 AC: 293 AN: 59678

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0143 AC: 2124 AN: 148034 Hom.: 20 Cov.: 29 AF XY: 0.0135 AC XY: 974 AN XY: 72030

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

African (AFR) AF: 0.0419 AC: 1665 AN: 39754

American (AMR) AF: 0.00715 AC: 106 AN: 14830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.0181 AC: 88 AN: 4856

South Asian (SAS) AF: 0.00389 AC: 18 AN: 4630

European-Finnish (FIN) AF: 0.0000992 AC: 1 AN: 10078

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.00336 AC: 226 AN: 67194

Other (OTH) AF: 0.00927 AC: 19 AN: 2050

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000314 Hom.: 30

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 11, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs3832105; hg19: chr2-223066017;