12-120213939-A-T

Position:

• chr12-120213939-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001385981.1(PXN):​c.2882T>A​(p.Met961Lys) 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: 33)
• Consequence: PXN NM_001385981.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.13

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PXN	NM_001385981.1	c.2882T>A	p.Met961Lys	missense_variant	14/15	ENST00000637617.2	NP_001372910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PXN	ENST00000637617.2	c.2882T>A	p.Met961Lys	missense_variant	14/15	5	NM_001385981.1	ENSP00000489840	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Jun 05, 2024

The c.1412T>A (p.M471K) alteration is located in exon 11 (coding exon 11) of the PXN gene. This alteration results from a T to A substitution at nucleotide position 1412, causing the methionine (M) at amino acid position 471 to be replaced by a lysine (K). 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	0.86
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.84	.;.;D;.;D;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Uncertain	0.0066	D
MutationAssessor	Benign	0.43	.;.;N;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	D;D;D;D;D;.
REVEL	Pathogenic	0.76
Sift	Uncertain	0.023	D;D;D;D;D;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;.
Polyphen		0.54	P;.;B;B;.;.
Vest4		0.84
MutPred		0.56		.;.;Gain of catalytic residue at F469 (P = 0.0046);.;.;.;
MVP		0.93
MPC		1.0
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.76
gMVP		0.82

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: rs1260925000; hg19: chr12-120651742;