2-222201414-G-A

Variant names:

• chr2-222201414-G-A
• rs757964568
• ENST00000344493.9:c.1202C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_181460.4(PAX3):​c.1202C>T​(p.Ser401Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,744 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (2 hom.)
• Consequence: PAX3 NM_181460.4 missense, splice_region
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.951
• 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: G2P, Orphanet, 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• Waardenburg syndrome type 3

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• 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: 1.7537 (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=0.017596334).
• BP6: Variant 2-222201414-G-A is Benign according to our data. Variant chr2-222201414-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 227834.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000132 (20/151944) while in subpopulation EAS AF = 0.00155 (8/5162). AF 95% confidence interval is 0.000771. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181460.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	NM_181458.4	MANE Select	c.1449C>T	p.Ile483Ile	synonymous	Exon 9 of 9	NP_852123.1	P23760-7
	PAX3	NM_181461.4		c.1202C>T	p.Ser401Leu	missense	Exon 8 of 8	NP_852126.1	P23760-4
	PAX3	NM_181460.4		c.1202C>T	p.Ser401Leu	missense splice_region	Exon 8 of 9	NP_852125.1	P23760-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000344493.9	TSL:1	c.1202C>T	p.Ser401Leu	missense	Exon 8 of 8	ENSP00000342092.4	P23760-4
	PAX3	ENST00000336840.11	TSL:1	c.1202C>T	p.Ser401Leu	missense splice_region	Exon 8 of 9	ENSP00000338767.5	P23760-5
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.1449C>T	p.Ile483Ile	synonymous	Exon 9 of 9	ENSP00000375922.3	P23760-7

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151944 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00155

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000140 AC: 35 AN: 250390 AF XY: 0.0000812

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1461800 Hom.: 2 Cov.: 34 AF XY: 0.000164 AC XY: 119 AN XY: 727200

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.000142 AC: 158 AN: 1111972

Other (OTH) AF: 0.00139 AC: 84 AN: 60388

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151944 Hom.: 0 Cov.: 31 AF XY: 0.0000943 AC XY: 7 AN XY: 74206

African (AFR) AF: 0.0000726 AC: 3 AN: 41346

American (AMR) AF: 0.0000656 AC: 1 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68018

Other (OTH) AF: 0.000958 AC: 2 AN: 2088

Alfa AF: 0.000355 Hom.: 1

Bravo AF: 0.000200

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	9.0
DANN	Benign	0.90
Eigen	Benign	0.12
Eigen_PC	Benign	0.087
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.070	D
PhyloP100		0.95
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.49
Sift	Benign	0.12	T
Sift4G	Benign	0.092	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.37		Gain of catalytic residue at S401 (P = 0.011)
MVP		0.55
ClinPred		0.045	T
GERP RS		0.85
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs757964568; hg19: chr2-223066133;