2-222201298-ACCC-ACCCC

Variant names:

• chr2-222201298-A-AC
• rs3832105
• NM_181458.4:c.*109dupG

Variant summary

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

The NM_181458.4(PAX3):​c.*109dupG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0876 in 1,595,896 control chromosomes in the GnomAD database, including 11,430 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (2521 hom., cov: 29)
  • Exomes 𝑓: 0.082 (8909 hom.)
• Consequence: PAX3 NM_181458.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.00
• 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):

• 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 2-222201298-A-AC is Benign according to our data. Variant chr2-222201298-A-AC is described in ClinVar as Benign. ClinVar VariationId is 1264428.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.57 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.*109dupG		3_prime_UTR	Exon 9 of 9	NP_852123.1	P23760-7
	PAX3	NM_001127366.3		c.*109dupG		3_prime_UTR	Exon 9 of 9	NP_001120838.1	P23760-6
	PAX3	NM_181461.4		c.*105dupG		3_prime_UTR	Exon 8 of 8	NP_852126.1	P23760-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.*109dupG		3_prime_UTR	Exon 9 of 9	ENSP00000375922.3	P23760-7
	PAX3	ENST00000336840.11	TSL:1	c.1205-59dupG		intron	N/A	ENSP00000338767.5	P23760-5
	PAX3	ENST00000392069.6	TSL:5	c.1452-59dupG		intron	N/A	ENSP00000375921.2	P23760-8

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21237 AN: 147866 Hom.: 2520 Cov.: 29

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.587

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0962

Gnomad NFE AF: 0.0493

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.0819 AC: 118563 AN: 1447932 Hom.: 8909 Cov.: 34 AF XY: 0.0848 AC XY: 61135 AN XY: 720522

African (AFR) AF: 0.235 AC: 7714 AN: 32800

American (AMR) AF: 0.206 AC: 9086 AN: 44106

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 2831 AN: 25954

East Asian (EAS) AF: 0.556 AC: 19744 AN: 35480

South Asian (SAS) AF: 0.203 AC: 17324 AN: 85422

European-Finnish (FIN) AF: 0.122 AC: 6380 AN: 52194

Middle Eastern (MID) AF: 0.125 AC: 714 AN: 5730

European-Non Finnish (NFE) AF: 0.0435 AC: 48151 AN: 1106578

Other (OTH) AF: 0.111 AC: 6619 AN: 59668

GnomAD4 genome AF: 0.144 AC: 21277 AN: 147964 Hom.: 2521 Cov.: 29 AF XY: 0.152 AC XY: 10942 AN XY: 71938

African (AFR) AF: 0.236 AC: 9407 AN: 39838

American (AMR) AF: 0.180 AC: 2659 AN: 14776

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 398 AN: 3440

East Asian (EAS) AF: 0.588 AC: 2843 AN: 4836

South Asian (SAS) AF: 0.226 AC: 1044 AN: 4618

European-Finnish (FIN) AF: 0.123 AC: 1230 AN: 10030

Middle Eastern (MID) AF: 0.0966 AC: 28 AN: 290

European-Non Finnish (NFE) AF: 0.0493 AC: 3313 AN: 67176

Other (OTH) AF: 0.147 AC: 301 AN: 2050

Alfa AF: 0.0285 Hom.: 30

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		0.0
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: rs3832105; hg19: chr2-223066017;