chr10-132697865-A-C

Position:

• chr10-132697865-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005539.5(INPP5A):​c.420A>C​(p.Leu140Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

Genes affected

INPP5A (HGNC:6076): (inositol polyphosphate-5-phosphatase A) The protein encoded by this gene is a membrane-associated type I inositol 1,4,5-trisphosphate (InsP3) 5-phosphatase. InsP3 5-phosphatases hydrolyze Ins(1,4,5)P3, which mobilizes intracellular calcium and acts as a second messenger mediating cell responses to various stimulation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5A	NM_005539.5	c.420A>C	p.Leu140Phe	missense_variant	6/16	ENST00000368594.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5A	ENST00000368594.8	c.420A>C	p.Leu140Phe	missense_variant	6/16	1	NM_005539.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2024

The c.420A>C (p.L140F) alteration is located in exon 6 (coding exon 6) of the INPP5A gene. This alteration results from a A to C substitution at nucleotide position 420, causing the leucine (L) at amino acid position 140 to be replaced by a phenylalanine (F). 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	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.64	D;T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.57
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.011	D;D;T
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.65
MutPred		0.68		Loss of catalytic residue at L140 (P = 0.0875);Loss of catalytic residue at L140 (P = 0.0875);.;
MVP		0.38
MPC		1.6
ClinPred		0.95	D
GERP RS		-0.48
Varity_R		0.33
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-134511369;