1-18634312-C-G

Variant names:

• chr1-18634312-C-G
• rs145325556
• NM_001135254.2:c.95C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001135254.2(PAX7):​c.95C>G​(p.Pro32Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PAX7 NM_001135254.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.89
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

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.95C>G	p.Pro32Arg	missense	Exon 2 of 9	NP_001128726.1	P23759-3
	PAX7	NM_002584.3		c.95C>G	p.Pro32Arg	missense	Exon 2 of 8	NP_002575.1	P23759-1
	PAX7	NM_013945.3		c.95C>G	p.Pro32Arg	missense	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.95C>G	p.Pro32Arg	missense	Exon 2 of 9	ENSP00000403389.2	P23759-3
	PAX7	ENST00000375375.7	TSL:1	c.95C>G	p.Pro32Arg	missense	Exon 2 of 8	ENSP00000364524.3	P23759-1
	PAX7	ENST00000400661.3	TSL:1	c.95C>G	p.Pro32Arg	missense	Exon 2 of 8	ENSP00000383502.3	P23759-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461320 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726932

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53214

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

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111852

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.081	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.34		Gain of MoRF binding (P = 0.0031)
MVP		0.85
MPC		1.3
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.44
gMVP		0.75
Mutation Taster		=29/71	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: rs145325556; hg19: chr1-18960806;