2-222201034-T-TAC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_181458.4(PAX3):​c.*372_*373dupGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0173 in 793,502 control chromosomes in the GnomAD database, including 581 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.051 (553 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (28 hom.)
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• 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):

• Waardenburg syndrome

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

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• craniofacial-deafness-hand syndrome

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Waardenburg syndrome type 3

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 2-222201034-T-TAC is Benign according to our data. Variant chr2-222201034-T-TAC is described in ClinVar as Benign. ClinVar VariationId is 1291395.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181458.4. 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.*372_*373dupGT		3_prime_UTR	Exon 9 of 9	NP_852123.1	P23760-7
	PAX3	NM_181459.4		c.*138_*139dupGT		3_prime_UTR	Exon 10 of 10	NP_852124.1	P23760-8
	PAX3	NM_001127366.3		c.*372_*373dupGT		3_prime_UTR	Exon 9 of 9	NP_001120838.1	P23760-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.*372_*373dupGT		3_prime_UTR	Exon 9 of 9	ENSP00000375922.3	P23760-7
	PAX3	ENST00000392069.6	TSL:5	c.*138_*139dupGT		3_prime_UTR	Exon 10 of 10	ENSP00000375921.2	P23760-8
	PAX3	ENST00000336840.11	TSL:1	c.*185_*186dupGT		downstream_gene	N/A	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes AF: 0.0512 AC: 7641 AN: 149178 Hom.: 554 Cov.: 31

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0280

Gnomad ASJ AF: 0.0304

Gnomad EAS AF: 0.00255

Gnomad SAS AF: 0.00235

Gnomad FIN AF: 0.00312

Gnomad MID AF: 0.00323

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.0472

GnomAD4 exome AF: 0.00946 AC: 6096 AN: 644230 Hom.: 28 Cov.: 2 AF XY: 0.00842 AC XY: 2805 AN XY: 333214

African (AFR) AF: 0.147 AC: 2472 AN: 16788

American (AMR) AF: 0.0155 AC: 449 AN: 28894

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 458 AN: 16366

East Asian (EAS) AF: 0.00190 AC: 56 AN: 29486

South Asian (SAS) AF: 0.00227 AC: 115 AN: 50708

European-Finnish (FIN) AF: 0.00402 AC: 150 AN: 37280

Middle Eastern (MID) AF: 0.0113 AC: 44 AN: 3902

European-Non Finnish (NFE) AF: 0.00408 AC: 1751 AN: 428864

Other (OTH) AF: 0.0188 AC: 601 AN: 31942

GnomAD4 genome AF: 0.0513 AC: 7658 AN: 149272 Hom.: 553 Cov.: 31 AF XY: 0.0491 AC XY: 3573 AN XY: 72778

African (AFR) AF: 0.165 AC: 6765 AN: 40882

American (AMR) AF: 0.0280 AC: 419 AN: 14966

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 104 AN: 3418

East Asian (EAS) AF: 0.00236 AC: 12 AN: 5090

South Asian (SAS) AF: 0.00214 AC: 10 AN: 4678

European-Finnish (FIN) AF: 0.00312 AC: 31 AN: 9928

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.00327 AC: 219 AN: 67040

Other (OTH) AF: 0.0468 AC: 97 AN: 2074

Alfa AF: 0.000743 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs373626774; hg19: chr2-223065753;