14-92941668-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_014216.6(ITPK1):c.1138G>A(p.Gly380Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,540,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ITPK1 NM_014216.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.310

Genes affected

ITPK1 (HGNC:6177): (inositol-tetrakisphosphate 1-kinase) This gene encodes an enzyme that belongs to the inositol 1,3,4-trisphosphate 5/6-kinase family. This enzyme regulates the synthesis of inositol tetraphosphate, and downstream products, inositol pentakisphosphate and inositol hexakisphosphate. Inositol metabolism plays a role in the development of the neural tube. Disruptions in this gene are thought to be associated with neural tube defects. A pseudogene of this gene has been identified on chromosome X. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.007348478).
• BP6: Variant 14-92941668-C-T is Benign according to our data. Variant chr14-92941668-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2355712.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ITPK1	NM_014216.6	c.1138G>A	p.Gly380Ser	missense_variant	11/11	ENST00000267615.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPK1	ENST00000267615.11	c.1138G>A	p.Gly380Ser	missense_variant	11/11	1	NM_014216.6	P1
ITPK1	ENST00000556603.6	c.1138G>A	p.Gly380Ser	missense_variant	11/11	1		P1
ITPK1	ENST00000555495.5	c.781G>A	p.Gly261Ser	missense_variant	9/9	1
ITPK1	ENST00000354313.7	c.902-3142G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 29 AN: 134848 Hom.: 0 AF XY: 0.000230 AC XY: 17 AN XY: 73814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000947

Gnomad SAS exome AF: 0.000846

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000124 AC: 172 AN: 1388048 Hom.: 0 Cov.: 35 AF XY: 0.000158 AC XY: 108 AN XY: 684862

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000280

Gnomad4 ASJ exome AF: 0.0000399

Gnomad4 EAS exome AF: 0.0000561

Gnomad4 SAS exome AF: 0.000947

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000715

Gnomad4 OTH exome AF: 0.000121

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74500

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.000173 AC: 16

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.32
Dann	Benign	0.64
DEOGEN2	Benign	0.081	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.018	N
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.0073	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.26	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.23	N;N;N
REVEL	Benign	0.030
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.0040	B;B;.
Vest4		0.046
MutPred		0.15		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);.;
MVP		0.12
MPC		0.43
ClinPred		0.022	T
GERP RS		-5.1
Varity_R		0.030
gMVP		0.15

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

Publications

LitVar

Other links and lift over

dbSNP: rs574548381; hg19: chr14-93408013;