rs1379006499

Variant names:

• chr2-222294310-G-T
• rs1379006499
• NM_181458.4:c.452-9C>A

Your query was ambiguous. Multiple possible variants found:

• chr2-222294310-G-T
• chr2-222294310-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_181458.4(PAX3):​c.452-9C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX3 NM_181458.4 intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: -0.488
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 2-222294310-G-T is Pathogenic according to our data. Variant chr2-222294310-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547740.

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.452-9C>A		intron	N/A	NP_852123.1	P23760-7
	PAX3	NM_181459.4		c.452-9C>A		intron	N/A	NP_852124.1	P23760-8
	PAX3	NM_001127366.3		c.449-9C>A		intron	N/A	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.452-9C>A		intron	N/A	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.449-9C>A		intron	N/A	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.452-9C>A		intron	N/A	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
1	-	-	Waardenburg syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.90
PhyloP100		-0.49

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: -2
DS_AL_spliceai		0.99		Position offset: -9

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

Other links and lift over

dbSNP: rs1379006499; hg19: chr2-223159029;