12-120215008-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001385981.1(PXN):c.2575-10T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,612,298 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (15 hom.)
• Consequence: PXN NM_001385981.1 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001677
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.423

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-120215008-A-C is Benign according to our data. Variant chr12-120215008-A-C is described in ClinVar as [Benign]. Clinvar id is 710179.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00799 (1216/152144) while in subpopulation AFR AF= 0.028 (1162/41498). AF 95% confidence interval is 0.0267. There are 9 homozygotes in gnomad4. There are 560 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1214 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PXN	NM_001385981.1	c.2575-10T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000637617.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PXN	ENST00000637617.2	c.2575-10T>G		splice_polypyrimidine_tract_variant, intron_variant		5	NM_001385981.1	A2

Frequencies

GnomAD3 genomes AF: 0.00799 AC: 1214 AN: 152026 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00214 AC: 522 AN: 244016 Hom.: 5 AF XY: 0.00161 AC XY: 214 AN XY: 132704

Gnomad AFR exome AF: 0.0310

Gnomad AMR exome AF: 0.00130

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000817

Gnomad OTH exome AF: 0.00118

GnomAD4 exome AF: 0.000811 AC: 1184 AN: 1460154 Hom.: 15 Cov.: 31 AF XY: 0.000722 AC XY: 524 AN XY: 726224

Gnomad4 AFR exome AF: 0.0290

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000930

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00159

GnomAD4 genome AF: 0.00799 AC: 1216 AN: 152144 Hom.: 9 Cov.: 32 AF XY: 0.00753 AC XY: 560 AN XY: 74366

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00587 Hom.: 1

Bravo AF: 0.00891

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	17
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00017
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.010		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: rs186612390; hg19: chr12-120652811;