2-222201758-C-T

Variant names:

• chr2-222201758-C-T
• rs78035924
• NM_181458.4:c.1420+186G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS1

The NM_181457.4(PAX3):​c.*166G>A variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.0000196 in 1,477,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000067 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PAX3 NM_181457.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 3.95
• Publications: 1 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):

• Waardenburg syndrome

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

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• craniofacial-deafness-hand syndrome

  Inheritance: Unknown, AD Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• Waardenburg syndrome type 3

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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-222201758-C-T is Benign according to our data. Variant chr2-222201758-C-T is described in ClinVar as Benign. ClinVar VariationId is 894955.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000143 (19/1328466) while in subpopulation AFR AF = 0.000652 (19/29142). AF 95% confidence interval is 0.000427. There are 0 homozygotes in GnomAdExome4. There are 9 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181457.4. 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.1420+186G>A		intron	N/A	NP_852123.1	P23760-7
	PAX3	NM_181457.4		c.*166G>A		3_prime_UTR	Exon 8 of 8	NP_852122.1	P23760-1
	PAX3	NM_181459.4		c.1420+186G>A		intron	N/A	NP_852124.1	P23760-8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX3	ENST00000392070.7	TSL:1 MANE Select	c.1420+186G>A		intron	N/A	ENSP00000375922.3	P23760-7
	PAX3	ENST00000409551.7	TSL:1	c.1417+186G>A		intron	N/A	ENSP00000386750.3	P23760-6
	PAX3	ENST00000336840.11	TSL:1	c.1174-316G>A		intron	N/A	ENSP00000338767.5	P23760-5

Frequencies

GnomAD3 genomes AF: 0.0000670 AC: 10 AN: 149312 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 19 AN: 1328466 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 9 AN XY: 650944

African (AFR) AF: 0.000652 AC: 19 AN: 29142

American (AMR) AF: 0.00 AC: 0 AN: 25028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20914

East Asian (EAS) AF: 0.00 AC: 0 AN: 35562

South Asian (SAS) AF: 0.00 AC: 0 AN: 66278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3712

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1056140

Other (OTH) AF: 0.00 AC: 0 AN: 55162

GnomAD4 genome AF: 0.0000669 AC: 10 AN: 149428 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 2 AN XY: 72664

African (AFR) AF: 0.000247 AC: 10 AN: 40426

American (AMR) AF: 0.00 AC: 0 AN: 14928

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5090

South Asian (SAS) AF: 0.00 AC: 0 AN: 4750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67678

Other (OTH) AF: 0.00 AC: 0 AN: 2070

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000102

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Craniofacial-deafness-hand syndrome (1)
-	-	1	Waardenburg syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.92
PhyloP100		4.0

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: rs78035924; hg19: chr2-223066477;