2-222201817-CA-C

Variant names:

• chr2-222201817-CA-C
• rs368725878
• NM_181458.4:c.1420+126delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_181458.4(PAX3):​c.1420+126delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,230,762 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 24)
  • Exomes 𝑓: 0.12 (0 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: 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 -2 ACMG points.

• BP6: Variant 2-222201817-CA-C is Benign according to our data. Variant chr2-222201817-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 1216859.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.1420+126delT		intron_variant	Intron 8 of 8	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.1420+126delT		intron_variant	Intron 8 of 8	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.00323 AC: 410 AN: 127118 Hom.: 1 Cov.: 24

Gnomad AFR AF: 0.00524

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00252

Gnomad ASJ AF: 0.000974

Gnomad EAS AF: 0.00133

Gnomad SAS AF: 0.00369

Gnomad FIN AF: 0.00988

Gnomad MID AF: 0.00368

Gnomad NFE AF: 0.00153

Gnomad OTH AF: 0.00581

GnomAD4 exome AF: 0.119 AC: 131169 AN: 1103586 Hom.: 0 Cov.: 0 AF XY: 0.121 AC XY: 66288 AN XY: 547914

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

African (AFR) AF: 0.147 AC: 3526 AN: 23922

American (AMR) AF: 0.186 AC: 5384 AN: 28950

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 2628 AN: 19996

East Asian (EAS) AF: 0.138 AC: 4167 AN: 30150

South Asian (SAS) AF: 0.130 AC: 8439 AN: 64814

European-Finnish (FIN) AF: 0.154 AC: 5845 AN: 38030

Middle Eastern (MID) AF: 0.121 AC: 398 AN: 3300

European-Non Finnish (NFE) AF: 0.112 AC: 95122 AN: 848456

Other (OTH) AF: 0.123 AC: 5660 AN: 45968

⚠️ 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: 0.00323 AC: 411 AN: 127176 Hom.: 1 Cov.: 24 AF XY: 0.00344 AC XY: 210 AN XY: 61060

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

African (AFR) AF: 0.00526 AC: 179 AN: 34058

American (AMR) AF: 0.00252 AC: 31 AN: 12312

Ashkenazi Jewish (ASJ) AF: 0.000974 AC: 3 AN: 3080

East Asian (EAS) AF: 0.00133 AC: 6 AN: 4514

South Asian (SAS) AF: 0.00370 AC: 15 AN: 4056

European-Finnish (FIN) AF: 0.00988 AC: 76 AN: 7694

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

European-Non Finnish (NFE) AF: 0.00153 AC: 90 AN: 58708

Other (OTH) AF: 0.00575 AC: 10 AN: 1738

⚠️ 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: 0.00 Hom.: 110

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 10, 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		-0.47
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: rs368725878; hg19: chr2-223066536; COSMIC: COSV60586342; COSMIC: COSV60586342;