Genetic Variant PSTPIP2:p.His234Arg (chr18-45993645-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_024430.4(PSTPIP2):c.701A>G(p.His234Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PSTPIP2
NM_024430.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.88

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:

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ACMG classification

Classification was made for transcript

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, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP2	NM_024430.4 link	c.701A>G	p.His234Arg	missense_variant	Exon 10 of 15	ENST00000409746.5	NP_077748.3	Q9H939-1A0A0S2Z4R2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PSTPIP2	ENST00000409746.5 link	c.701A>G	p.His234Arg	missense_variant	Exon 10 of 15	1	NM_024430.4	ENSP00000387261.4	Q9H939-1
PSTPIP2	ENST00000589328.5 link	c.701A>G	p.His234Arg	missense_variant	Exon 10 of 14	1		ENSP00000468622.1	Q9H939-2
PSTPIP2	ENST00000593086.1 link	n.330A>G		non_coding_transcript_exon_variant	Exon 1 of 3	3
PSTPIP2	ENST00000588801.5 link	n.657+5149A>G		intron_variant	Intron 8 of 8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461874

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727238

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 05, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.701A>G (p.H234R) alteration is located in exon 10 (coding exon 10) of the PSTPIP2 gene. This alteration results from a A to G substitution at nucleotide position 701, causing the histidine (H) at amino acid position 234 to be replaced by an arginine (R). 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

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

.;D

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Pathogenic

3.2

M;M

PhyloP100

4.9

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.8

.;D

REVEL

Uncertain

0.42

Sift

Uncertain

0.0080

.;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.74

MutPred

0.76

Gain of MoRF binding (P = 0.0193);Gain of MoRF binding (P = 0.0193);

MVP

0.62

MPC

1.2

ClinPred

0.99

GERP RS

5.6

Varity_R

0.63

gMVP

0.89

Mutation Taster

=62/38

polymorphism

(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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chr18-45993645-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over