2-222201518-G-A

Variant names:

• chr2-222201518-G-A
• rs13014735
• NM_181458.4:c.1421-76C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_181458.4(PAX3):​c.1421-76C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0846 in 1,563,452 control chromosomes in the GnomAD database, including 7,453 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.071 (616 hom., cov: 31)
  • Exomes 𝑓: 0.086 (6837 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.48
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 2-222201518-G-A is Benign according to our data. Variant chr2-222201518-G-A is described in ClinVar as [Benign]. Clinvar id is 1246737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.1421-76C>T		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.1421-76C>T		intron_variant	Intron 8 of 8	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.0706 AC: 10740 AN: 152066 Hom.: 614 Cov.: 31

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.0352

Gnomad EAS AF: 0.0148

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.0741

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0820

Gnomad OTH AF: 0.0700

GnomAD4 exome AF: 0.0861 AC: 121497 AN: 1411268 Hom.: 6837 Cov.: 24 AF XY: 0.0870 AC XY: 61367 AN XY: 705654

African (AFR) AF: 0.0127 AC: 410 AN: 32380

American (AMR) AF: 0.280 AC: 12463 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.0345 AC: 889 AN: 25790

East Asian (EAS) AF: 0.0132 AC: 520 AN: 39336

South Asian (SAS) AF: 0.147 AC: 12515 AN: 85142

European-Finnish (FIN) AF: 0.0774 AC: 4127 AN: 53318

Middle Eastern (MID) AF: 0.0655 AC: 365 AN: 5570

European-Non Finnish (NFE) AF: 0.0805 AC: 85828 AN: 1066512

Other (OTH) AF: 0.0746 AC: 4380 AN: 58674

GnomAD4 genome AF: 0.0706 AC: 10739 AN: 152184 Hom.: 616 Cov.: 31 AF XY: 0.0732 AC XY: 5448 AN XY: 74382

African (AFR) AF: 0.0162 AC: 671 AN: 41546

American (AMR) AF: 0.176 AC: 2694 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0352 AC: 122 AN: 3468

East Asian (EAS) AF: 0.0145 AC: 75 AN: 5178

South Asian (SAS) AF: 0.137 AC: 659 AN: 4816

European-Finnish (FIN) AF: 0.0741 AC: 785 AN: 10596

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0820 AC: 5577 AN: 67990

Other (OTH) AF: 0.0693 AC: 146 AN: 2108

Alfa AF: 0.0808 Hom.: 93

Bravo AF: 0.0767

Asia WGS AF: 0.0590 AC: 203 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		2.5
Mutation Taster		=99/1	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: rs13014735; hg19: chr2-223066237;