1-18634437-C-T

Variant names:

• chr1-18634437-C-T
• rs1176071790
• NM_001135254.2:c.220C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001135254.2(PAX7):​c.220C>T​(p.Arg74*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PAX7 NM_001135254.2 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.01
• Publications: 2 publications found

Genes affected

PAX7 (HGNC:8621): (paired box 7) This gene is a member of the paired box (PAX) family of transcription factors. Members of this gene family typically contain a paired box domain, an octapeptide, and a paired-type homeodomain. These genes play critical roles during fetal development and cancer growth. The specific function of the paired box 7 gene is unknown but speculated to involve tumor suppression since fusion of this gene with a forkhead domain family member has been associated with alveolar rhabdomyosarcoma. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2008]

PAX7 Gene-Disease associations (from GenCC):

• myopathy, congenital, progressive, with scoliosis

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics
• congenital myopathy with myasthenic-like onset

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-18634437-C-T is Pathogenic according to our data. Variant chr1-18634437-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 689508.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135254.2. 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
	PAX7	NM_001135254.2	MANE Select	c.220C>T	p.Arg74*	stop_gained	Exon 2 of 9	NP_001128726.1	P23759-3
	PAX7	NM_002584.3		c.220C>T	p.Arg74*	stop_gained	Exon 2 of 8	NP_002575.1	P23759-1
	PAX7	NM_013945.3		c.220C>T	p.Arg74*	stop_gained	Exon 2 of 8	NP_039236.1	P23759-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAX7	ENST00000420770.7	TSL:1 MANE Select	c.220C>T	p.Arg74*	stop_gained	Exon 2 of 9	ENSP00000403389.2	P23759-3
	PAX7	ENST00000375375.7	TSL:1	c.220C>T	p.Arg74*	stop_gained	Exon 2 of 8	ENSP00000364524.3	P23759-1
	PAX7	ENST00000400661.3	TSL:1	c.220C>T	p.Arg74*	stop_gained	Exon 2 of 8	ENSP00000383502.3	P23759-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251274 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Myopathy, congenital, progressive, with scoliosis (3)
1	-	-	Alveolar rhabdomyosarcoma;C5231417:Myopathy, congenital, progressive, with scoliosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	48
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		2.0
Vest4		0.94
GERP RS		5.3
Mutation Taster		=4/196	disease causing (ClinVar)

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: rs1176071790; hg19: chr1-18960931;