2-222202200-C-G

Position:

chr2-222202200-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_181458.4(PAX3):c.1174-10G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.129 in 1,566,748 control chromosomes in the GnomAD database, including 14,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1207 hom., cov: 31)

Exomes 𝑓: 0.13 ( 13028 hom. )

Consequence

PAX3
NM_181458.4 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001188

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.14

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 2-222202200-C-G is Benign according to our data. Variant chr2-222202200-C-G is described in ClinVar as [Benign]. Clinvar id is 226998.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX3	NM_181458.4 linkuse as main transcript	c.1174-10G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 linkuse as main transcript	c.1174-10G>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_181458.4	ENSP00000375922	A1	P23760-7

Frequencies

GnomAD3 genomes

AF:

0.116

AC:

17619

AN:

152038

Hom.:

1208

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0795

Gnomad AMI

AF:

0.0614

Gnomad AMR

AF:

0.145

Gnomad ASJ

AF:

0.188

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0334

Gnomad FIN

AF:

0.118

Gnomad MID

AF:

0.155

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.151

GnomAD3 exomes

AF:

0.108

AC:

20972

AN:

194398

Hom.:

1403

AF XY:

0.106

AC XY:

10948

AN XY:

103678

show subpopulations

Gnomad AFR exome

AF:

0.0738

Gnomad AMR exome

AF:

0.0928

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.000280

Gnomad SAS exome

AF:

0.0379

Gnomad FIN exome

AF:

0.116

Gnomad NFE exome

AF:

0.145

Gnomad OTH exome

AF:

0.144

GnomAD4 exome

AF:

0.130

AC:

184477

AN:

1414592

Hom.:

13028

Cov.:

AF XY:

0.128

AC XY:

89666

AN XY:

701240

show subpopulations

Gnomad4 AFR exome

AF:

0.0809

Gnomad4 AMR exome

AF:

0.0977

Gnomad4 ASJ exome

AF:

0.192

Gnomad4 EAS exome

AF:

0.000158

Gnomad4 SAS exome

AF:

0.0372

Gnomad4 FIN exome

AF:

0.115

Gnomad4 NFE exome

AF:

0.144

Gnomad4 OTH exome

AF:

0.133

GnomAD4 genome

AF:

0.116

AC:

17609

AN:

152156

Hom.:

1207

Cov.:

AF XY:

0.114

AC XY:

8505

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0792

Gnomad4 AMR

AF:

0.145

Gnomad4 ASJ

AF:

0.188

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0332

Gnomad4 FIN

AF:

0.118

Gnomad4 NFE

AF:

0.142

Gnomad4 OTH

AF:

0.149

Alfa

AF:

0.0940

Hom.:

182

Bravo

AF:

0.117

Asia WGS

AF:

0.0250

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	1174-10G>C in intron 7C of PAX3: This variant is not expected to have clinical s ignificance because it has been identified in 14.6% (1259/8598) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs2855268). -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Craniofacial-deafness-hand syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

DANN

Benign

0.70

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.0020

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over