12-120221639-G-A

Variant summary

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

The NM_001385981.1(PXN):c.815C>T(p.Ser272Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000156 in 1,410,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: PXN NM_001385981.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05

Genes affected

PXN (HGNC:9718): (paxillin) This gene encodes a cytoskeletal protein involved in actin-membrane attachment at sites of cell adhesion to the extracellular matrix (focal adhesion). Alternatively spliced transcript variants encoding different isoforms have been described for this gene. These isoforms exhibit different expression pattern, and have different biochemical, as well as physiological properties (PMID:9054445). [provided by RefSeq, Aug 2011]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXN	NM_001385981.1	c.815C>T	p.Ser272Leu	missense_variant	6/15	ENST00000637617.2
LOC124903034	XR_007063486.1	n.1160G>A		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXN	ENST00000637617.2	c.815C>T	p.Ser272Leu	missense_variant	6/15	5	NM_001385981.1	A2
	ENST00000651205.1	n.1321G>A		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000177 AC: 3 AN: 169716 Hom.: 0 AF XY: 0.0000332 AC XY: 3 AN XY: 90340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000142

Gnomad OTH exome AF: 0.000215

GnomAD4 exome AF: 0.0000156 AC: 22 AN: 1410324 Hom.: 0 Cov.: 31 AF XY: 0.0000172 AC XY: 12 AN XY: 696716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000109

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.0000342

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000257 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000170 AC: 2

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

Dec 06, 2022

The c.815C>T (p.S272L) alteration is located in exon 6 (coding exon 6) of the PXN gene. This alteration results from a C to T substitution at nucleotide position 815, causing the serine (S) at amino acid position 272 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	0.95
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D
M_CAP	Benign	0.085	D
MetaRNN	Uncertain	0.60	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M;.;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.2	D;D;D;D;D;.;.
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D;D;D;D;D;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;.;.
Polyphen		0.99	D;.;D;P;.;.;.
Vest4		0.53
MutPred		0.36		Loss of phosphorylation at S272 (P = 0.0323);.;Loss of phosphorylation at S272 (P = 0.0323);Loss of phosphorylation at S272 (P = 0.0323);.;Loss of phosphorylation at S272 (P = 0.0323);.;
MVP		0.88
MPC		1.5
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.59
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs752094289; hg19: chr12-120659442; COSMIC: COSV105056664; COSMIC: COSV105056664;