2-98520695-C-T

Variant names:

• chr2-98520695-C-T
• rs1574887674
• NM_001134225.2:c.115C>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001134225.2(INPP4A):​c.115C>T​(p.Gln39*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000149 in 1,343,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: INPP4A NM_001134225.2 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.04
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-98520695-C-T is Pathogenic according to our data. Variant chr2-98520695-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 801338.Status of the report is no_assertion_criteria_provided, 0 stars.

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.115C>T	p.Gln39*	stop_gained	Exon 4 of 25	NP_001127697.1	Q96PE3-3
	INPP4A	NM_001351425.2	MANE Plus Clinical	c.115C>T	p.Gln39*	stop_gained	Exon 4 of 26	NP_001338354.1	A0ABB0MUY6
	INPP4A	NM_001134224.2		c.115C>T	p.Gln39*	stop_gained	Exon 4 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.115C>T	p.Gln39*	stop_gained	Exon 4 of 25	ENSP00000386777.4	Q96PE3-3
	INPP4A	ENST00000715854.1	MANE Plus Clinical	c.115C>T	p.Gln39*	stop_gained	Exon 4 of 26	ENSP00000520526.1	A0ABB0MUY6
	INPP4A	ENST00000523221.2	TSL:1	c.115C>T	p.Gln39*	stop_gained	Exon 4 of 26	ENSP00000427722.1	Q96PE3-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1343344 Hom.: 0 Cov.: 24 AF XY: 0.00000150 AC XY: 1 AN XY: 665530

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

African (AFR) AF: 0.00 AC: 0 AN: 29804

American (AMR) AF: 0.00 AC: 0 AN: 32882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24742

East Asian (EAS) AF: 0.00 AC: 0 AN: 36310

South Asian (SAS) AF: 0.0000134 AC: 1 AN: 74566

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5534

European-Non Finnish (NFE) AF: 9.67e-7 AC: 1 AN: 1033830

Other (OTH) AF: 0.00 AC: 0 AN: 56124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		5.0
Vest4		0.52
GERP RS		4.9
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1574887674; hg19: chr2-99137158;