2-222259374-A-G

Variant names:

• chr2-222259374-A-G
• rs4674639
• NM_181458.4:c.587-27091T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181458.4(PAX3):​c.587-27091T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,190 control chromosomes in the GnomAD database, including 3,575 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.20 (3575 hom., cov: 32)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.353 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	NM_181458.4	MANE Select	c.587-27091T>C		intron	N/A	NP_852123.1
	PAX3	NM_181459.4		c.587-27091T>C		intron	N/A	NP_852124.1
	PAX3	NM_001127366.3		c.584-27091T>C		intron	N/A	NP_001120838.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.587-27091T>C		intron	N/A	ENSP00000375922.3
	PAX3	ENST00000409551.7	TSL:1	c.584-27091T>C		intron	N/A	ENSP00000386750.3
	PAX3	ENST00000336840.11	TSL:1	c.587-27091T>C		intron	N/A	ENSP00000338767.5

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30252 AN: 152072 Hom.: 3564 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.197

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.200

Gnomad OTH AF: 0.201

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.199 AC: 30272 AN: 152190 Hom.: 3575 Cov.: 32 AF XY: 0.206 AC XY: 15340 AN XY: 74394

African (AFR) AF: 0.110 AC: 4557 AN: 41544

American (AMR) AF: 0.333 AC: 5097 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.197 AC: 685 AN: 3470

East Asian (EAS) AF: 0.367 AC: 1898 AN: 5174

South Asian (SAS) AF: 0.349 AC: 1684 AN: 4820

European-Finnish (FIN) AF: 0.213 AC: 2251 AN: 10582

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.200 AC: 13613 AN: 67998

Other (OTH) AF: 0.200 AC: 422 AN: 2108

Alfa AF: 0.204 Hom.: 14604

Bravo AF: 0.204

Asia WGS AF: 0.351 AC: 1218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	11
DANN	Benign	0.67
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs4674639; hg19: chr2-223124093;