chr18-45999461-A-T

Variant names:

• chr18-45999461-A-T
• NM_024430.4:c.491T>A

Variant summary

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

The NM_024430.4(PSTPIP2):​c.491T>A​(p.Leu164Gln) variant causes a missense 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. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PSTPIP2 NM_024430.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.376
• 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 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	c.491T>A	p.Leu164Gln	missense_variant	Exon 7 of 15	ENST00000409746.5	NP_077748.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PSTPIP2	ENST00000409746.5	c.491T>A	p.Leu164Gln	missense_variant	Exon 7 of 15	1	NM_024430.4	ENSP00000387261.4
PSTPIP2	ENST00000589328.5	c.491T>A	p.Leu164Gln	missense_variant	Exon 7 of 14	1		ENSP00000468622.1
PSTPIP2	ENST00000588801.5	n.586T>A		non_coding_transcript_exon_variant	Exon 7 of 9	5
PSTPIP2	ENST00000591729.1	n.567T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.491T>A (p.L164Q) alteration is located in exon 7 (coding exon 7) of the PSTPIP2 gene. This alteration results from a T to A substitution at nucleotide position 491, causing the leucine (L) at amino acid position 164 to be replaced by a glutamine (Q). 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	0.099
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.061	.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.086	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L
PhyloP100		0.38
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.1	.;N
REVEL	Benign	0.041
Sift	Benign	0.064	.;T
Sift4G	Benign	0.40	T;T
Polyphen		0.98	D;P
Vest4		0.28
MutPred		0.25		Loss of stability (P = 0.0313);Loss of stability (P = 0.0313);
MVP		0.45
MPC		0.36
ClinPred		0.22	T
GERP RS		0.081
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.13
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: -1

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

Other links and lift over

hg19: chr18-43579427;