2-98520098-T-C

Variant names:

• chr2-98520098-T-C
• rs777671884
• NM_001134225.2:c.50T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001134225.2(INPP4A):​c.50T>C​(p.Met17Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000589 in 1,578,450 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M17V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: INPP4A NM_001134225.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85
• Publications: 0 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: 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=0.11287433).

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.50T>C	p.Met17Thr	missense	Exon 3 of 25	NP_001127697.1	Q96PE3-3
	INPP4A	NM_001351425.2	MANE Plus Clinical	c.50T>C	p.Met17Thr	missense	Exon 3 of 26	NP_001338354.1	A0ABB0MUY6
	INPP4A	NM_001134224.2		c.50T>C	p.Met17Thr	missense	Exon 3 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.50T>C	p.Met17Thr	missense	Exon 3 of 25	ENSP00000386777.4	Q96PE3-3
	INPP4A	ENST00000715854.1	MANE Plus Clinical	c.50T>C	p.Met17Thr	missense	Exon 3 of 26	ENSP00000520526.1	A0ABB0MUY6
	INPP4A	ENST00000523221.2	TSL:1	c.50T>C	p.Met17Thr	missense	Exon 3 of 26	ENSP00000427722.1	Q96PE3-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000414 AC: 8 AN: 193186 AF XY: 0.0000578

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000547

Gnomad NFE exome AF: 0.0000861

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000645 AC: 92 AN: 1426278 Hom.: 0 Cov.: 31 AF XY: 0.0000694 AC XY: 49 AN XY: 706238

African (AFR) AF: 0.0000305 AC: 1 AN: 32742

American (AMR) AF: 0.00 AC: 0 AN: 40310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25544

East Asian (EAS) AF: 0.00 AC: 0 AN: 37886

South Asian (SAS) AF: 0.00 AC: 0 AN: 81400

European-Finnish (FIN) AF: 0.0000393 AC: 2 AN: 50840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000814 AC: 89 AN: 1092886

Other (OTH) AF: 0.00 AC: 0 AN: 58942

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000105 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000167 AC: 2

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	0.18
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.080
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.017	D
Polyphen		0.0010	B
Vest4		0.33
MutPred		0.33		Gain of glycosylation at M17 (P = 0.0075)
MVP		0.10
MPC		0.59
ClinPred		0.15	T
GERP RS		5.5
PromoterAI		0.055	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.27
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs777671884; hg19: chr2-99136561;