12-120224174-T-C

Variant names:

• chr12-120224174-T-C
• rs4767884
• NM_001385981.1:c.217A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001385981.1(PXN):​c.217A>G​(p.Ser73Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.796 in 1,593,326 control chromosomes in the GnomAD database, including 508,349 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (53937 hom., cov: 31)
  • Exomes 𝑓: 0.79 (454412 hom.)
• Consequence: PXN NM_001385981.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0780
• Publications: 42 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]

LOC124903034 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.473439E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.963 is higher than 0.05.

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.217A>G	p.Ser73Gly	missense	Exon 2 of 15	NP_001372910.1	A0A1B0GTU4
	PXN	NM_001385982.1		c.217A>G	p.Ser73Gly	missense	Exon 2 of 14	NP_001372911.1
	PXN	NM_001385983.1		c.217A>G	p.Ser73Gly	missense	Exon 2 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.217A>G	p.Ser73Gly	missense	Exon 2 of 15	ENSP00000489840.1	A0A1B0GTU4
	PXN	ENST00000228307.11	TSL:1	c.217A>G	p.Ser73Gly	missense	Exon 2 of 12	ENSP00000228307.7	P49023-1
	PXN	ENST00000424649.6	TSL:1	c.217A>G	p.Ser73Gly	missense	Exon 2 of 11	ENSP00000391283.2	P49023-2

Frequencies

GnomAD3 genomes AF: 0.838 AC: 127340 AN: 151952 Hom.: 53874 Cov.: 31

Gnomad AFR AF: 0.947

Gnomad AMI AF: 0.887

Gnomad AMR AF: 0.817

Gnomad ASJ AF: 0.847

Gnomad EAS AF: 0.986

Gnomad SAS AF: 0.908

Gnomad FIN AF: 0.768

Gnomad MID AF: 0.816

Gnomad NFE AF: 0.770

Gnomad OTH AF: 0.836

GnomAD2 exomes AF: 0.831 AC: 179716 AN: 216210 AF XY: 0.830

Gnomad AFR exome AF: 0.952

Gnomad AMR exome AF: 0.861

Gnomad ASJ exome AF: 0.845

Gnomad EAS exome AF: 0.986

Gnomad FIN exome AF: 0.771

Gnomad NFE exome AF: 0.773

Gnomad OTH exome AF: 0.808

GnomAD4 exome AF: 0.792 AC: 1141412 AN: 1441256 Hom.: 454412 Cov.: 50 AF XY: 0.794 AC XY: 568119 AN XY: 715082

African (AFR) AF: 0.955 AC: 31728 AN: 33206

American (AMR) AF: 0.856 AC: 35267 AN: 41188

Ashkenazi Jewish (ASJ) AF: 0.843 AC: 21472 AN: 25462

East Asian (EAS) AF: 0.987 AC: 38436 AN: 38950

South Asian (SAS) AF: 0.898 AC: 75438 AN: 84044

European-Finnish (FIN) AF: 0.771 AC: 39834 AN: 51694

Middle Eastern (MID) AF: 0.857 AC: 4851 AN: 5660

European-Non Finnish (NFE) AF: 0.768 AC: 845889 AN: 1101426

Other (OTH) AF: 0.813 AC: 48497 AN: 59626

GnomAD4 genome AF: 0.838 AC: 127464 AN: 152070 Hom.: 53937 Cov.: 31 AF XY: 0.840 AC XY: 62380 AN XY: 74304

African (AFR) AF: 0.947 AC: 39304 AN: 41516

American (AMR) AF: 0.818 AC: 12489 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.847 AC: 2942 AN: 3472

East Asian (EAS) AF: 0.986 AC: 5078 AN: 5150

South Asian (SAS) AF: 0.908 AC: 4365 AN: 4806

European-Finnish (FIN) AF: 0.768 AC: 8114 AN: 10570

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.770 AC: 52360 AN: 67974

Other (OTH) AF: 0.837 AC: 1764 AN: 2108

Alfa AF: 0.799 Hom.: 216761

Bravo AF: 0.847

TwinsUK AF: 0.777 AC: 2880

ALSPAC AF: 0.750 AC: 2891

ESP6500AA AF: 0.944 AC: 3593

ESP6500EA AF: 0.777 AC: 6378

ExAC AF: 0.817 AC: 97636

Asia WGS AF: 0.938 AC: 3260 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.59
DANN	Benign	0.16
DEOGEN2	Benign	0.17	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.088	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.078
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.030
Sift	Benign	0.88	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.054
ClinPred		0.0039	T
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.13
Mutation Taster		=100/0	polymorphism (auto)

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: rs4767884; hg19: chr12-120661977; COSMIC: COSV107196020; COSMIC: COSV107196020;