chr2-222221236-G-T

Variant names:

• chr2-222221236-G-T
• rs2234675
• NM_181458.4:c.944C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 9.60
• Publications: 20 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)

LOC107985991 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 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: 1.7934 (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=0.005897939).
• 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 VariationId is 218940.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 76 AR,AD,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181458.4. 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.944C>A	p.Thr315Lys	missense	Exon 6 of 9	NP_852123.1	P23760-7
	PAX3	NM_181459.4		c.944C>A	p.Thr315Lys	missense	Exon 6 of 10	NP_852124.1	P23760-8
	PAX3	NM_001127366.3		c.941C>A	p.Thr314Lys	missense	Exon 6 of 9	NP_001120838.1	P23760-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.944C>A	p.Thr315Lys	missense	Exon 6 of 9	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.941C>A	p.Thr314Lys	missense	Exon 6 of 9	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.944C>A	p.Thr315Lys	missense	Exon 6 of 9	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3855 AN: 152124 Hom.: 76 Cov.: 32

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

GnomAD2 exomes AF: 0.0268 AC: 6723 AN: 251172 AF XY: 0.0271

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 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.: 31 AF XY: 0.0365 AC XY: 26518 AN XY: 727126

African (AFR) AF: 0.00547 AC: 183 AN: 33470

American (AMR) AF: 0.0143 AC: 640 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0223 AC: 584 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0205 AC: 1770 AN: 86258

European-Finnish (FIN) AF: 0.0381 AC: 2036 AN: 53420

Middle Eastern (MID) AF: 0.0161 AC: 93 AN: 5766

European-Non Finnish (NFE) AF: 0.0418 AC: 46465 AN: 1111762

Other (OTH) AF: 0.0317 AC: 1917 AN: 60382

GnomAD4 genome AF: 0.0253 AC: 3854 AN: 152242 Hom.: 76 Cov.: 32 AF XY: 0.0246 AC XY: 1834 AN XY: 74448

African (AFR) AF: 0.00652 AC: 271 AN: 41554

American (AMR) AF: 0.0133 AC: 203 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.0178 AC: 86 AN: 4820

European-Finnish (FIN) AF: 0.0371 AC: 394 AN: 10610

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0402 AC: 2737 AN: 68002

Other (OTH) AF: 0.0199 AC: 42 AN: 2106

Alfa AF: 0.0347 Hom.: 347

Bravo AF: 0.0231

TwinsUK AF: 0.0383 AC: 142

ALSPAC AF: 0.0402 AC: 155

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0379 AC: 326

ExAC AF: 0.0266 AC: 3235

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0403

EpiControl AF: 0.0334

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	1	-	Congenital diaphragmatic hernia (1)
-	-	1	Craniofacial-deafness-hand syndrome (1)
-	-	1	Waardenburg syndrome (1)
-	-	1	Waardenburg syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0059	T
MetaSVM	Uncertain	0.072	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.17	T
Polyphen		0.84	P
Vest4		0.27
MPC		0.79
ClinPred		0.031	T
GERP RS		6.1
Varity_R		0.30
gMVP		0.49
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2234675; hg19: chr2-223085955; COSMIC: COSV100399889;