rs151199924

chr2-222220310-G-Achr2-222220310-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_181458.4(PAX3):c.1003C>T(p.Pro335Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000724 in 1,614,090 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00050 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00075 ( 19 hom. )

Consequence

PAX3
NM_181458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 9.57

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:

LOC107985991 (HGNC:):

LOC107985991 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009261638).

BP6

Variant 2-222220310-G-A is Benign according to our data. Variant chr2-222220310-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 226993.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000499 (76/152300) while in subpopulation SAS AF= 0.0154 (74/4818). AF 95% confidence interval is 0.0125. There are 1 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome at 7 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4 linkuse as main transcript	c.1003C>T	p.Pro335Ser	missense_variant	7/9	ENST00000392070.7
LOC107985991	XR_001739903.2 linkuse as main transcript	n.240-86G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7 linkuse as main transcript	c.1003C>T	p.Pro335Ser	missense_variant	7/9	1	NM_181458.4	A1	P23760-7

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0151

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00150

AC:

378

AN:

251358

Hom.:

AF XY:

0.00205

AC XY:

278

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0121

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000748

AC:

1093

AN:

1461790

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

775

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000499

AC:

AN:

152300

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0154

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000125

Hom.:

Bravo

AF:

0.0000982

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00152

AC:

185

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Usher syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 20, 2016

p.Pro334Ser in exon 7 of PAX3: This variant is not expected to have clinical sig nificance because it has been identified in 1.1% (182/16510) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs151199924). -

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. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 17, 2023

- -

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

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.094

BayesDel_noAF

Uncertain

0.10

Cadd

Uncertain

Dann

Pathogenic

1.0

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

MetaRNN

Benign

0.0093

T;T;T;T;T;T

MetaSVM

Uncertain

0.75

MutationAssessor

Uncertain

2.1

M;M;M;M;.;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-3.9

D;D;D;D;D;D

REVEL

Uncertain

0.64

Sift

Uncertain

0.017

D;D;D;D;D;D

Sift4G

Benign

0.22

T;T;T;T;T;T

Polyphen

1.0, 1.0

.;.;D;D;.;D

Vest4

0.55

MVP

0.77

MPC

1.3

ClinPred

0.081

GERP RS

5.7

Varity_R

0.30

gMVP

0.61

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

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