dbSNP rs1060505039: INPP5K:p.Met93Val (chr17-1509784-T-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_016532.4(INPP5K):c.277A>G(p.Met93Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M93I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

INPP5K
NM_016532.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.79

Publications

1 publications found

Variant links:

Genes affected

INPP5K (HGNC:33882): (inositol polyphosphate-5-phosphatase K) This gene encodes a protein with 5-phosphatase activity toward polyphosphate inositol. The protein localizes to the cytosol in regions lacking actin stress fibers. It is thought that this protein may negatively regulate the actin cytoskeleton. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

INPP5K Gene-Disease associations (from GenCC):

congenital muscular dystrophy with cataracts and intellectual disability
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
Marinesco-Sjogren syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

INPP5K links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 17-1509784-T-C is Pathogenic according to our data. Variant chr17-1509784-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 417779.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016532.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INPP5K	NM_016532.4	MANE Select	c.277A>G	p.Met93Val	missense	Exon 4 of 12	NP_057616.2
INPP5K	NM_001135642.2		c.49A>G	p.Met17Val	missense	Exon 6 of 14	NP_001129114.1	Q9BT40-2
INPP5K	NM_130766.3		c.49A>G	p.Met17Val	missense	Exon 5 of 13	NP_570122.1	Q9BT40-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INPP5K	ENST00000421807.7	TSL:1 MANE Select	c.277A>G	p.Met93Val	missense	Exon 4 of 12	ENSP00000413937.2	Q9BT40-1
INPP5K	ENST00000449479.5	TSL:2	c.1A>G	p.Met1?	start_lost	Exon 3 of 7	ENSP00000413259.1	C9JZB0
INPP5K	ENST00000498390.5	TSL:4	c.1A>G	p.Met1?	start_lost	Exon 4 of 4	ENSP00000466929.1	K7ENF7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital muscular dystrophy with cataracts and intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.90

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

PhyloP100

5.8

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.5

REVEL

Pathogenic

0.87

Sift

Benign

0.049

Sift4G

Uncertain

0.022

Polyphen

0.12

Vest4

0.85

MutPred

0.71

Loss of sheet (P = 0.1501)

MVP

0.96

MPC

0.39

ClinPred

0.98

GERP RS

5.3

Varity_R

0.74

gMVP

0.93

Mutation Taster

=8/192

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over