10-132777774-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005539.5(INPP5A):c.1081G>C(p.Val361Leu) 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. 15/21 in silico tools predict a benign outcome for this variant. 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: 0.153

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123321146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5A	NM_005539.5	c.1081G>C	p.Val361Leu	missense_variant	13/16	ENST00000368594.8
INPP5A	NM_001321042.2	c.889G>C	p.Val297Leu	missense_variant	10/13
INPP5A	XM_017016204.2	c.907G>C	p.Val303Leu	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5A	ENST00000368594.8	c.1081G>C	p.Val361Leu	missense_variant	13/16	1	NM_005539.5	P1
INPP5A	ENST00000368593.7	c.1081G>C	p.Val361Leu	missense_variant	13/13	1
INPP5A	ENST00000342652.6	c.826G>C	p.Val276Leu	missense_variant	10/10	5
INPP5A	ENST00000445580.1	c.127G>C	p.Val43Leu	missense_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jul 19, 2022

The c.1081G>C (p.V361L) alteration is located in exon 13 (coding exon 13) of the INPP5A gene. This alteration results from a G to C substitution at nucleotide position 1081, causing the valine (V) at amino acid position 361 to be replaced by a leucine (L). 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	0.093
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Benign	0.33	T;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.15	N;.;.
MutationTaster	Benign	0.60	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.038
Sift	Benign	0.24	T;T;T
Sift4G	Benign	0.42	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.26
MutPred		0.58		Gain of relative solvent accessibility (P = 0.005);Gain of relative solvent accessibility (P = 0.005);.;
MVP		0.13
MPC		0.57
ClinPred		0.25	T
GERP RS		-0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.051
gMVP		0.46

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: chr10-134591278;