12-120213939-A-G

Variant names:

• chr12-120213939-A-G
• rs1260925000
• NM_001385981.1:c.2882T>C

Variant summary

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

The NM_001385981.1(PXN):​c.2882T>C​(p.Met961Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,236 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PXN NM_001385981.1 missense
• Clinical Significance: Not reported in ClinVar
• 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, 0.824

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PXN	NM_001385981.1	c.2882T>C	p.Met961Thr	missense_variant	Exon 14 of 15	ENST00000637617.2	NP_001372910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PXN	ENST00000637617.2	c.2882T>C	p.Met961Thr	missense_variant	Exon 14 of 15	5	NM_001385981.1	ENSP00000489840.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245810 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133540

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460236 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726194

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	.;.;D;.;D;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D
MetaSVM	Uncertain	0.0084	D
MutationAssessor	Benign	1.5	.;.;L;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-5.6	D;D;D;D;D;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;T;D;D;D;.
Polyphen		0.34	B;.;B;B;.;.
Vest4		0.82
MVP		0.94
MPC		0.80
ClinPred		0.95	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.72

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;