1-18635223-G-T

Position:

• chr1-18635223-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001135254.2(PAX7):​c.434G>T​(p.Arg145Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAX7 NM_001135254.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.15

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAX7	NM_001135254.2	c.434G>T	p.Arg145Leu	missense_variant	3/9	ENST00000420770.7	NP_001128726.1
PAX7	NM_002584.3	c.434G>T	p.Arg145Leu	missense_variant	3/8		NP_002575.1
PAX7	NM_013945.3	c.434G>T	p.Arg145Leu	missense_variant	3/8		NP_039236.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAX7	ENST00000420770.7	c.434G>T	p.Arg145Leu	missense_variant	3/9	1	NM_001135254.2	ENSP00000403389	P1
PAX7	ENST00000375375.7	c.434G>T	p.Arg145Leu	missense_variant	3/8	1		ENSP00000364524
PAX7	ENST00000400661.3	c.434G>T	p.Arg145Leu	missense_variant	3/8	1		ENSP00000383502

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

The c.434G>T (p.R145L) alteration is located in exon 3 (coding exon 3) of the PAX7 gene. This alteration results from a G to T substitution at nucleotide position 434, causing the arginine (R) at amino acid position 145 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	.;D;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.74	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.99, 0.91	.;D;P
Vest4		0.78
MutPred		0.57		Loss of disorder (P = 0.0435);Loss of disorder (P = 0.0435);Loss of disorder (P = 0.0435);
MVP		0.97
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.76
gMVP		0.53

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-18961717;