rs371082879

Variant names:

• chr12-120214929-C-G
• rs371082879
• NM_001385981.1:c.2644G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-120214929-C-G
• chr12-120214929-C-T

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.2644G>C​(p.Gly882Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,692 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PXN NM_001385981.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.84
• Publications: 0 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, 0.89

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.2644G>C	p.Gly882Arg	missense	Exon 12 of 15	NP_001372910.1	A0A1B0GTU4
	PXN	NM_001385982.1		c.2368G>C	p.Gly790Arg	missense	Exon 11 of 14	NP_001372911.1
	PXN	NM_001385983.1		c.2362G>C	p.Gly788Arg	missense	Exon 11 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.2644G>C	p.Gly882Arg	missense	Exon 12 of 15	ENSP00000489840.1	A0A1B0GTU4
	PXN	ENST00000228307.11	TSL:1	c.1174G>C	p.Gly392Arg	missense	Exon 9 of 12	ENSP00000228307.7	P49023-1
	PXN	ENST00000424649.6	TSL:1	c.1072G>C	p.Gly358Arg	missense	Exon 8 of 11	ENSP00000391283.2	P49023-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461692 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111860

Other (OTH) AF: 0.00 AC: 0 AN: 60374

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.60		Gain of catalytic residue at E389 (P = 0.0714)
MVP		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.81
gMVP		0.67
Mutation Taster		=53/47	polymorphism

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: rs371082879; hg19: chr12-120652732;