chr18-45993703-C-T

Variant names:

• chr18-45993703-C-T
• NM_024430.4:c.643G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024430.4(PSTPIP2):​c.643G>A​(p.Ala215Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/26 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSTPIP2 NM_024430.4 missense, splice_region
• Scores: Splicing: ADA: 0.01223
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12652057).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PSTPIP2	NM_024430.4	c.643G>A	p.Ala215Thr	missense_variant, splice_region_variant	Exon 10 of 15	ENST00000409746.5	NP_077748.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP2	ENST00000409746.5	c.643G>A	p.Ala215Thr	missense_variant, splice_region_variant	Exon 10 of 15	1	NM_024430.4	ENSP00000387261.4
PSTPIP2	ENST00000589328.5	c.643G>A	p.Ala215Thr	missense_variant, splice_region_variant	Exon 10 of 14	1		ENSP00000468622.1
PSTPIP2	ENST00000593086.1	n.272G>A		non_coding_transcript_exon_variant	Exon 1 of 3	3
PSTPIP2	ENST00000588801.5	n.657+5091G>A		intron_variant	Intron 8 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643G>A (p.A215T) alteration is located in exon 10 (coding exon 10) of the PSTPIP2 gene. This alteration results from a G to A substitution at nucleotide position 643, causing the alanine (A) at amino acid position 215 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	0.065
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.081	.;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.39	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L
PhyloP100		1.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.032
Sift	Benign	0.10	.;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0070	B;B
Vest4		0.14
MutPred		0.35		Gain of loop (P = 0.1069);Gain of loop (P = 0.1069);
MVP		0.39
MPC		0.33
ClinPred		0.14	T
GERP RS		3.4
Varity_R		0.031
gMVP		0.13
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.27
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr18-43573669;