10-132777693-C-T

Variant summary

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

The NM_005539.5(INPP5A):c.1000C>T(p.Arg334Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,612,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

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=0.17120302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5A	NM_005539.5	c.1000C>T	p.Arg334Cys	missense_variant	13/16	ENST00000368594.8
INPP5A	NM_001321042.2	c.808C>T	p.Arg270Cys	missense_variant	10/13
INPP5A	XM_017016204.2	c.826C>T	p.Arg276Cys	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5A	ENST00000368594.8	c.1000C>T	p.Arg334Cys	missense_variant	13/16	1	NM_005539.5	P1
INPP5A	ENST00000368593.7	c.1000C>T	p.Arg334Cys	missense_variant	13/13	1
INPP5A	ENST00000342652.6	c.745C>T	p.Arg249Cys	missense_variant	10/10	5
INPP5A	ENST00000445580.1	c.46C>T	p.Arg16Cys	missense_variant	2/5	5

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000156 AC: 39 AN: 249742 Hom.: 0 AF XY: 0.000148 AC XY: 20 AN XY: 135404

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.000800

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000187

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000128 AC: 187 AN: 1460592 Hom.: 0 Cov.: 31 AF XY: 0.000132 AC XY: 96 AN XY: 726594

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000379 Hom.: 0

Bravo AF: 0.000189

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000382

EpiControl AF: 0.000178

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 29, 2023

The c.1000C>T (p.R334C) alteration is located in exon 13 (coding exon 13) of the INPP5A gene. This alteration results from a C to T substitution at nucleotide position 1000, causing the arginine (R) at amino acid position 334 to be replaced by a cysteine (C). 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	0.071
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	0.61	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Uncertain	0.37
Sift	Uncertain	0.022	D;D;D
Sift4G	Uncertain	0.030	D;D;T
Polyphen		0.97	D;P;.
Vest4		0.32
MVP		0.43
MPC		0.94
ClinPred		0.067	T
GERP RS		0.43
Varity_R		0.077
gMVP		0.39

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

LitVar

Other links and lift over

dbSNP: rs150382081; hg19: chr10-134591197; COSMIC: COSV61249403;