2-98533401-C-T

Variant names:

• chr2-98533401-C-T
• rs199762176
• NM_001134225.2:c.176C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001134225.2(INPP4A):​c.176C>T​(p.Ser59Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000155 in 1,613,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: INPP4A NM_001134225.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87
• Publications: 4 publications found

Genes affected

INPP4A (HGNC:6074): (inositol polyphosphate-4-phosphatase type I A) This gene encodes an Mg++ independent enzyme that hydrolyzes the 4-position phosphate from the inositol ring of phosphatidylinositol 3,4-bisphosphate, inositol 1,3,4-trisphosphate, and inositol 3,4-bisphosphate. Multiple transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Aug 2008]

INPP4A Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21227378).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001134225.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP4A	NM_001134225.2	MANE Select	c.176C>T	p.Ser59Leu	missense	Exon 5 of 25	NP_001127697.1	Q96PE3-3
	INPP4A	NM_001351425.2	MANE Plus Clinical	c.176C>T	p.Ser59Leu	missense	Exon 5 of 26	NP_001338354.1	A0ABB0MUY6
	INPP4A	NM_001134224.2		c.176C>T	p.Ser59Leu	missense	Exon 5 of 26	NP_001127696.1	Q96PE3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INPP4A	ENST00000409851.8	TSL:1 MANE Select	c.176C>T	p.Ser59Leu	missense	Exon 5 of 25	ENSP00000386777.4	Q96PE3-3
	INPP4A	ENST00000715854.1	MANE Plus Clinical	c.176C>T	p.Ser59Leu	missense	Exon 5 of 26	ENSP00000520526.1	A0ABB0MUY6
	INPP4A	ENST00000523221.2	TSL:1	c.176C>T	p.Ser59Leu	missense	Exon 5 of 26	ENSP00000427722.1	Q96PE3-1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000683 AC: 17 AN: 248928 AF XY: 0.0000889

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000164 AC: 239 AN: 1460786 Hom.: 1 Cov.: 29 AF XY: 0.000167 AC XY: 121 AN XY: 726674

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000195 AC: 217 AN: 1111370

Other (OTH) AF: 0.000315 AC: 19 AN: 60348

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000945

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.0000579 AC: 7

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.9
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.087	T
Sift4G	Uncertain	0.055	T
Polyphen		0.90	P
Vest4		0.38
MVP		0.13
MPC		0.83
ClinPred		0.24	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.39
Mutation Taster		=55/45	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

dbSNP: rs199762176; hg19: chr2-99149864;