dbSNP rs140301287: INPP4B:p.Asp870Val (chr4-142082064-T-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_001101669.3(INPP4B):c.2609A>T(p.Asp870Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000754 in 1,326,324 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. D870A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

INPP4B
NM_001101669.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.67

Publications

0 publications found

Variant links:

Genes affected

INPP4B (HGNC:6075): (inositol polyphosphate-4-phosphatase type II B) INPP4B encodes the inositol polyphosphate 4-phosphatase type II, one of the enzymes involved in phosphatidylinositol signaling pathways. This enzyme removes the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate. There is limited data to suggest that the human type II enzyme is subject to alternative splicing, as has been established for the type I enzyme. [provided by RefSeq, Jul 2008]

INPP4B links:

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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;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001101669.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INPP4B	NM_001101669.3	MANE Select	c.2609A>T	p.Asp870Val	missense	Exon 25 of 26	NP_001095139.1	O15327-1
INPP4B	NM_001331040.1		c.2609A>T	p.Asp870Val	missense	Exon 25 of 26	NP_001317969.1	O15327
INPP4B	NM_001385335.1		c.2609A>T	p.Asp870Val	missense	Exon 24 of 25	NP_001372264.1	E7EQN9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
INPP4B	ENST00000262992.9	TSL:5 MANE Select	c.2609A>T	p.Asp870Val	missense	Exon 25 of 26	ENSP00000262992.4	O15327-1
INPP4B	ENST00000508116.5	TSL:1	c.2609A>T	p.Asp870Val	missense	Exon 24 of 25	ENSP00000423954.1	O15327-1
INPP4B	ENST00000513000.5	TSL:1	c.2609A>T	p.Asp870Val	missense	Exon 26 of 27	ENSP00000425487.1	O15327-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.54e-7

AC:

AN:

1326324

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648340

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:

32254

American (AMR)

AF:

0.00

AC:

AN:

43172

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23144

East Asian (EAS)

AF:

0.00

AC:

AN:

38228

South Asian (SAS)

AF:

0.0000161

AC:

AN:

62200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5216

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1021642

Other (OTH)

AF:

0.00

AC:

AN:

53334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.060

MetaRNN

Uncertain

0.62

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.3

PhyloP100

7.7

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.35

Sift

Uncertain

0.010

Sift4G

Uncertain

0.032

Polyphen

1.0

Vest4

0.95

MutPred

0.34

Gain of catalytic residue at D870 (P = 0.05)

MVP

0.58

MPC

0.91

ClinPred

0.99

GERP RS

6.1

Varity_R

0.54

gMVP

0.80

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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