chr10-132607946-A-C

Variant names:

• chr10-132607946-A-C
• NM_005539.5:c.107A>C

Variant summary

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

The NM_005539.5(INPP5A):​c.107A>C​(p.Glu36Ala) 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: 34)
• Consequence: INPP5A NM_005539.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.46
• Publications: 0 publications found

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

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
INPP5A	NM_005539.5	c.107A>C	p.Glu36Ala	missense_variant	Exon 2 of 16	ENST00000368594.8	NP_005530.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5A	ENST00000368594.8	c.107A>C	p.Glu36Ala	missense_variant	Exon 2 of 16	1	NM_005539.5	ENSP00000357583.3
INPP5A	ENST00000368593.7	c.107A>C	p.Glu36Ala	missense_variant	Exon 2 of 13	1		ENSP00000357582.3
INPP5A	ENST00000342652.6	c.20A>C	p.Glu7Ala	missense_variant	Exon 1 of 10	5		ENSP00000340707.6
INPP5A	ENST00000423490.5	c.65A>C	p.Glu22Ala	missense_variant	Exon 2 of 6	5		ENSP00000390936.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.107A>C (p.E36A) alteration is located in exon 2 (coding exon 2) of the INPP5A gene. This alteration results from a A to C substitution at nucleotide position 107, causing the glutamic acid (E) at amino acid position 36 to be replaced by an alanine (A). 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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.66	D;D;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.099	D
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	2.0	M;.;.
PhyloP100		1.5
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.17	T;T;T
Polyphen		0.29	B;P;.
Vest4		0.33
MutPred		0.64		Gain of MoRF binding (P = 0.0526);Gain of MoRF binding (P = 0.0526);.;
MVP		0.45
MPC		1.2
ClinPred		0.97	D
GERP RS		4.2
PromoterAI		0.043	Neutral
Varity_R		0.42
gMVP		0.50
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

hg19: chr10-134421450;