Genetic Variant PAX7:p.Pro112Gln (chr1-18635124-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001135254.2(PAX7):c.335C>A(p.Pro112Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,300 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. P112L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PAX7
NM_001135254.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.88

Publications

0 publications found

Variant links:

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

PAX7 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.951

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAX7	NM_001135254.2	MANE Select	c.335C>A	p.Pro112Gln	missense	Exon 3 of 9	NP_001128726.1	P23759-3
PAX7	NM_002584.3		c.335C>A	p.Pro112Gln	missense	Exon 3 of 8	NP_002575.1	P23759-1
PAX7	NM_013945.3		c.335C>A	p.Pro112Gln	missense	Exon 3 of 8	NP_039236.1	P23759-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAX7	ENST00000420770.7	TSL:1 MANE Select	c.335C>A	p.Pro112Gln	missense	Exon 3 of 9	ENSP00000403389.2	P23759-3
PAX7	ENST00000375375.7	TSL:1	c.335C>A	p.Pro112Gln	missense	Exon 3 of 8	ENSP00000364524.3	P23759-1
PAX7	ENST00000400661.3	TSL:1	c.335C>A	p.Pro112Gln	missense	Exon 3 of 8	ENSP00000383502.3	P23759-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461300

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86156

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111682

Other (OTH)

AF:

0.00

AC:

AN:

60346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.95

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.84

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.2

PhyloP100

7.9

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0040

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.78

MutPred

0.78

Loss of phosphorylation at T111 (P = 0.0742)

MVP

0.93

MPC

1.1

ClinPred

0.99

GERP RS

4.9

Varity_R

0.72

gMVP

0.52

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over