10-132697858-A-G

Variant summary

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

The NM_005539.5(INPP5A):c.413A>G(p.Asp138Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,706 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.68

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=0.21902856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INPP5A	NM_005539.5	c.413A>G	p.Asp138Gly	missense_variant	6/16	ENST00000368594.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INPP5A	ENST00000368594.8	c.413A>G	p.Asp138Gly	missense_variant	6/16	1	NM_005539.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461706 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Sep 22, 2022

The c.413A>G (p.D138G) alteration is located in exon 6 (coding exon 6) of the INPP5A gene. This alteration results from a A to G substitution at nucleotide position 413, causing the aspartic acid (D) at amino acid position 138 to be replaced by a glycine (G). 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	0.23
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	20
Dann	Benign	0.18
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.026
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.66	N;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.7	N;N;N
REVEL	Benign	0.26
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.14	B;D;.
Vest4		0.51
MutPred		0.54		Loss of ubiquitination at K133 (P = 0.0517);Loss of ubiquitination at K133 (P = 0.0517);.;
MVP		0.36
MPC		1.7
ClinPred		0.82	D
GERP RS		5.1
Varity_R		0.22
gMVP		0.64

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: rs1049684899; hg19: chr10-134511362;