2-222201724-G-A

Variant names:

• chr2-222201724-G-A
• rs45624434
• NM_181458.4:c.1420+220C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_181458.4(PAX3):​c.1420+220C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,459,256 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: PAX3 NM_181458.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 2.73
• Publications: 1 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=-0.38).
• BP6: Variant 2-222201724-G-A is Benign according to our data. Variant chr2-222201724-G-A is described in ClinVar as [Benign]. Clinvar id is 334551.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0104 (1578/151486) while in subpopulation AFR AF = 0.0359 (1481/41252). AF 95% confidence interval is 0.0344. There are 23 homozygotes in GnomAd4. There are 743 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 23 AR,AD,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.1420+220C>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.1420+220C>T		intron_variant	Intron 8 of 8	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1568 AN: 151370 Hom.: 23 Cov.: 31

Gnomad AFR AF: 0.0358

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00508

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00529

GnomAD4 exome AF: 0.00110 AC: 1433 AN: 1307770 Hom.: 27 Cov.: 30 AF XY: 0.00101 AC XY: 646 AN XY: 638446

African (AFR) AF: 0.0416 AC: 1195 AN: 28754

American (AMR) AF: 0.00252 AC: 58 AN: 22984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19840

East Asian (EAS) AF: 0.00 AC: 0 AN: 35270

South Asian (SAS) AF: 0.000331 AC: 21 AN: 63408

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32288

Middle Eastern (MID) AF: 0.000272 AC: 1 AN: 3674

European-Non Finnish (NFE) AF: 0.0000420 AC: 44 AN: 1047144

Other (OTH) AF: 0.00210 AC: 114 AN: 54408

GnomAD4 genome AF: 0.0104 AC: 1578 AN: 151486 Hom.: 23 Cov.: 31 AF XY: 0.0100 AC XY: 743 AN XY: 73946

African (AFR) AF: 0.0359 AC: 1481 AN: 41252

American (AMR) AF: 0.00507 AC: 77 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10378

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67960

Other (OTH) AF: 0.00666 AC: 14 AN: 2102

Alfa AF: 0.00540 Hom.: 3

Bravo AF: 0.0119

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Craniofacial-deafness-hand syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Waardenburg syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.82
PhyloP100		2.7
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: rs45624434; hg19: chr2-223066443;