Genetic Variant ENST00000589328.5:c.819G>A (chr18-45991906-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000589328.5(PSTPIP2):c.819G>A(p.Trp273*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000193 in 1,605,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

PSTPIP2
ENST00000589328.5 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.496

Publications

0 publications found

Variant links:

Genes affected

PSTPIP2 (HGNC:9581): (proline-serine-threonine phosphatase interacting protein 2) Predicted to enable actin filament binding activity. Predicted to be involved in actin filament polymerization. Predicted to be located in cytoskeleton and membrane. Predicted to be active in actin filament; cytoplasm; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

PSTPIP2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP2	NM_024430.4 link	c.916G>A	p.Ala306Thr	missense_variant	Exon 12 of 15	ENST00000409746.5	NP_077748.3	Q9H939-1A0A0S2Z4R2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSTPIP2	ENST00000589328.5 link	c.819G>A	p.Trp273*	stop_gained	Exon 11 of 14	1		ENSP00000468622.1	Q9H939-2
PSTPIP2	ENST00000409746.5 link	c.916G>A	p.Ala306Thr	missense_variant	Exon 12 of 15	1	NM_024430.4	ENSP00000387261.4	Q9H939-1
PSTPIP2	ENST00000588801.5 link	n.657+6888G>A		intron_variant	Intron 8 of 8	5
PSTPIP2	ENST00000593086.1 link	n.*30G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000201

AC:

AN:

248242

AF XY:

0.0000223

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1453628

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

723598

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33160

American (AMR)

AF:

0.00

AC:

AN:

43984

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25986

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

85628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.0000244

AC:

AN:

1105952

Other (OTH)

AF:

0.00

AC:

AN:

60132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41424

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000957

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.916G>A (p.A306T) alteration is located in exon 12 (coding exon 12) of the PSTPIP2 gene. This alteration results from a G to A substitution at nucleotide position 916, causing the alanine (A) at amino acid position 306 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.044

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.70

MetaRNN

Benign

0.069

MetaSVM

Benign

-0.88

PhyloP100

0.50

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.15

REVEL

Benign

0.053

Sift

Benign

0.42

Sift4G

Benign

0.32

Polyphen

0.0020

Vest4

0.14

MVP

0.38

MPC

0.33

ClinPred

0.53

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.47

Mutation Taster

=43/157

disease causing (fs/PTC)

(source)

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

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ENST00000589328.5:c.819G>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over