NM_181458.4:c.1195C>G

Variant names:

• chr2-222202169-G-C
• rs1553568937
• NM_181458.4:c.1195C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 3P and 9B. PM2 PP2 BP4 BP6_Very_Strong

The NM_181458.4(PAX3):​c.1195C>G​(p.His399Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H399H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PAX3 NM_181458.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.60
• Publications: 0 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):

• craniofacial-deafness-hand syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• Waardenburg syndrome type 1

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 47 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: 1.618 (below the threshold of 3.09). Trascript score misZ: 1.7934 (below the threshold of 3.09). GenCC associations: The gene is linked to Waardenburg syndrome type 3, Waardenburg syndrome type 1, Waardenburg syndrome, craniofacial-deafness-hand syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37707734).
• BP6: Variant 2-222202169-G-C is Benign according to our data. Variant chr2-222202169-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 488039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAX3	NM_181458.4	c.1195C>G	p.His399Asp	missense_variant	Exon 8 of 9	ENST00000392070.7	NP_852123.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAX3	ENST00000392070.7	c.1195C>G	p.His399Asp	missense_variant	Exon 8 of 9	1	NM_181458.4	ENSP00000375922.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Waardenburg syndrome type 1 Benign:1

Mar 01, 2017

Laboratory of Human Genetics, Universidade de São Paulo

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;.;.;T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.38	T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.0	N;N;.;N
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.9	N;N;N;N
REVEL	Uncertain	0.52
Sift	Benign	0.069	T;D;D;D
Sift4G	Benign	0.20	T;T;T;T
Polyphen		0.24	.;.;.;B
Vest4		0.69
MutPred		0.36		Gain of relative solvent accessibility (P = 0.0166);Gain of relative solvent accessibility (P = 0.0166);.;Gain of relative solvent accessibility (P = 0.0166);
MVP		0.91
MPC		0.72
ClinPred		0.51	D
GERP RS		5.7
Varity_R		0.22
gMVP		0.51
Mutation Taster		=21/79	disease causing

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: rs1553568937; hg19: chr2-223066888;