rs1553592728

Positions:

• chr2-222294245-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_181458.4(PAX3):​c.508G>A​(p.Ala170Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A170D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.91

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20901197).
• BP6: Variant 2-222294245-C-T is Benign according to our data. Variant chr2-222294245-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 505427.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PAX3	NM_181458.4	c.508G>A	p.Ala170Thr	missense_variant	4/9	ENST00000392070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PAX3	ENST00000392070.7	c.508G>A	p.Ala170Thr	missense_variant	4/9	1	NM_181458.4	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 08, 2016

p.Ala170Thr in exon 4A of PAX3: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, Guinea pig, alpaca, and Bactrian camel have a threonine (Thr) at this posit ion despite high nearby amino acid conservation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.081
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.78	T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	0.69	N;N;N;N;.;N;N;N
MutationTaster	Benign	0.79	D;D;D;D;D;D;D;D
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.50	T;T;T;T;T;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0, 0.065	.;.;B;B;.;B;B;B
Vest4		0.27
MutPred		0.41		Gain of phosphorylation at A170 (P = 0.0081);Gain of phosphorylation at A170 (P = 0.0081);Gain of phosphorylation at A170 (P = 0.0081);Gain of phosphorylation at A170 (P = 0.0081);.;Gain of phosphorylation at A170 (P = 0.0081);Gain of phosphorylation at A170 (P = 0.0081);Gain of phosphorylation at A170 (P = 0.0081);
MVP		0.58
MPC		0.46
ClinPred		0.33	T
GERP RS		4.2
Varity_R		0.076
gMVP		0.26

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

Other links and lift over

dbSNP: rs1553592728; hg19: chr2-223158964;