Genetic Variant NM_005539.5:c.755T>C (chr10-132749539-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005539.5(INPP5A):c.755T>C(p.Met252Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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: 0.0000014 ( 0 hom. )

Consequence

INPP5A
NM_005539.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.68

Publications

0 publications found

Variant links:

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]

INPP5A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25812596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INPP5A	NM_005539.5 link	c.755T>C	p.Met252Thr	missense_variant	Exon 10 of 16	ENST00000368594.8	NP_005530.3	Q14642

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
INPP5A	ENST00000368594.8 link	c.755T>C	p.Met252Thr	missense_variant	Exon 10 of 16	1	NM_005539.5	ENSP00000357583.3	Q14642
INPP5A	ENST00000368593.7 link	c.755T>C	p.Met252Thr	missense_variant	Exon 10 of 13	1		ENSP00000357582.3	Q5T1B5
INPP5A	ENST00000498337.1 link	n.217T>C		non_coding_transcript_exon_variant	Exon 3 of 5	3
INPP5A	ENST00000342652.6 link	c.646-16234T>C		intron_variant	Intron 8 of 9	5		ENSP00000340707.6	H0Y2W5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460598

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726590

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52198

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111968

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.755T>C (p.M252T) alteration is located in exon 10 (coding exon 10) of the INPP5A gene. This alteration results from a T to C substitution at nucleotide position 755, causing the methionine (M) at amino acid position 252 to be replaced by a threonine (T). 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

0.26

BayesDel_addAF

Benign

0.0040

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.22

T;T

Eigen

Benign

-0.00035

Eigen_PC

Benign

0.095

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0092

MetaRNN

Benign

0.26

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

L;.

PhyloP100

5.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.16

Sift

Benign

0.64

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.42

B;B

Vest4

0.50

MutPred

0.55

Loss of sheet (P = 0.0483);Loss of sheet (P = 0.0483);

MVP

0.22

MPC

0.68

ClinPred

0.71

GERP RS

5.1

Varity_R

0.22

gMVP

0.64

Mutation Taster

=68/32

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over