NM_001385981.1:c.2887G>C

Variant names:

• chr12-120213934-C-G
• rs766217902
• NM_001385981.1:c.2887G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001385981.1(PXN):​c.2887G>C​(p.Ala963Pro) 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. 13/22 in silico tools predict a damaging 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. A963T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PXN NM_001385981.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001385981.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXN	NM_001385981.1	MANE Select	c.2887G>C	p.Ala963Pro	missense	Exon 14 of 15	NP_001372910.1	A0A1B0GTU4
	PXN	NM_001385982.1		c.2611G>C	p.Ala871Pro	missense	Exon 13 of 14	NP_001372911.1
	PXN	NM_001385983.1		c.2605G>C	p.Ala869Pro	missense	Exon 13 of 14	NP_001372912.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PXN	ENST00000637617.2	TSL:5 MANE Select	c.2887G>C	p.Ala963Pro	missense	Exon 14 of 15	ENSP00000489840.1	A0A1B0GTU4
	PXN	ENST00000228307.11	TSL:1	c.1417G>C	p.Ala473Pro	missense	Exon 11 of 12	ENSP00000228307.7	P49023-1
	PXN	ENST00000424649.6	TSL:1	c.1315G>C	p.Ala439Pro	missense	Exon 10 of 11	ENSP00000391283.2	P49023-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.59		Gain of catalytic residue at A473 (P = 0)
MVP		0.97
MPC		1.8
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.81
gMVP		0.90
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs766217902; hg19: chr12-120651737;