Genetic Variant NM_005539.5:c.727G>A (chr10-132726900-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_005539.5(INPP5A):c.727G>A(p.Val243Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,454,582 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V243L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

INPP5A
NM_005539.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.13

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:

ENSG00000293889 (HGNC:):

ENSG00000293889 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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 link	c.727G>A	p.Val243Met	missense_variant	Exon 9 of 16	ENST00000368594.8	NP_005530.3	Q14642

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INPP5A	ENST00000368594.8 link	c.727G>A	p.Val243Met	missense_variant	Exon 9 of 16	1	NM_005539.5	ENSP00000357583.3		Q14642

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1454582

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723214

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33300

American (AMR)

AF:

0.0000225

AC:

AN:

44350

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25994

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.00

AC:

AN:

85896

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1106526

Other (OTH)

AF:

0.00

AC:

AN:

60052

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

D;D

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.014

MetaRNN

Uncertain

0.46

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

1.7

L;.

PhyloP100

5.1

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.99

D;D

Vest4

0.48

MutPred

0.44

Loss of ubiquitination at K240 (P = 0.1828);Loss of ubiquitination at K240 (P = 0.1828);

MVP

0.31

MPC

0.86

ClinPred

0.93

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.56

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over