chr2-222221236-G-T

Position:

chr2-222221236-G-T

Variant summary

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

The NM_181458.4(PAX3):c.944C>A(p.Thr315Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 1,613,850 control chromosomes in the GnomAD database, including 1,249 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 0.025 ( 76 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1173 hom. )

Consequence

PAX3
NM_181458.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:8

Conservation

PhyloP100: 9.60

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=0.005897939).

BP6

Variant 2-222221236-G-T is Benign according to our data. Variant chr2-222221236-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218940.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=7, Uncertain_significance=1}. Variant chr2-222221236-G-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0253 (3854/152242) while in subpopulation NFE AF= 0.0402 (2737/68002). AF 95% confidence interval is 0.039. There are 76 homozygotes in gnomad4. There are 1834 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 76 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX3	NM_181458.4 linkuse as main transcript	c.944C>A	p.Thr315Lys	missense_variant	6/9	ENST00000392070.7	NP_852123.1
LOC107985991	XR_001739903.2 linkuse as main transcript	n.547G>T		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7 linkuse as main transcript	c.944C>A	p.Thr315Lys	missense_variant	6/9	1	NM_181458.4	ENSP00000375922	A1	P23760-7

Frequencies

GnomAD3 genomes

AF:

0.0253

AC:

3855

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00654

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0178

Gnomad FIN

AF:

0.0371

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0403

Gnomad OTH

AF:

0.0202

GnomAD3 exomes

AF:

0.0268

AC:

6723

AN:

251172

Hom.:

121

AF XY:

0.0271

AC XY:

3680

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.00547

Gnomad AMR exome

AF:

0.0135

Gnomad ASJ exome

AF:

0.0222

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0194

Gnomad FIN exome

AF:

0.0381

Gnomad NFE exome

AF:

0.0384

Gnomad OTH exome

AF:

0.0274

GnomAD4 exome

AF:

0.0367

AC:

53689

AN:

1461608

Hom.:

1173

Cov.:

AF XY:

0.0365

AC XY:

26518

AN XY:

727126

show subpopulations

Gnomad4 AFR exome

AF:

0.00547

Gnomad4 AMR exome

AF:

0.0143

Gnomad4 ASJ exome

AF:

0.0223

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0205

Gnomad4 FIN exome

AF:

0.0381

Gnomad4 NFE exome

AF:

0.0418

Gnomad4 OTH exome

AF:

0.0317

GnomAD4 genome

AF:

0.0253

AC:

3854

AN:

152242

Hom.:

Cov.:

AF XY:

0.0246

AC XY:

1834

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00652

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0178

Gnomad4 FIN

AF:

0.0371

Gnomad4 NFE

AF:

0.0402

Gnomad4 OTH

AF:

0.0199

Alfa

AF:

0.0361

Hom.:

174

Bravo

AF:

0.0231

TwinsUK

AF:

0.0383

AC:

142

ALSPAC

AF:

0.0402

AC:

155

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0379

AC:

326

ExAC

AF:

0.0266

AC:

3235

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0403

EpiControl

AF:

0.0334

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr314Lys in exon 6 of PAX3: This variant is not expected to have clinical signi ficance because it has been identified in 3.8% (326/8600) of European American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs2234675). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 08, 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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 20, 2018	- -

Congenital diaphragmatic hernia

Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Mar 03, 2015

It is unclear whether these changes, alone or in aggregate, are contributing to the development of CDH in this family. -

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 type 1

Benign:1

Likely benign, criteria provided, single submitter

research

Laboratory of Human Genetics, Universidade de São Paulo

Mar 01, 2017

- -

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

0.60

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.60

.;.;.;.;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;D;D;D;D

MetaRNN

Benign

0.0059

T;T;T;T;T;T

MetaSVM

Uncertain

0.072

MutationAssessor

Benign

1.8

L;L;L;L;.;L

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.6

D;D;N;N;D;D

REVEL

Uncertain

0.40

Sift

Uncertain

0.0080

D;D;D;D;D;D

Sift4G

Benign

0.17

T;T;T;T;T;T

Polyphen

0.84, 0.76, 0.62

.;.;P;P;.;P

Vest4

0.27

MPC

0.79

ClinPred

0.031

GERP RS

6.1

Varity_R

0.30

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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