14-92941626-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.1180G>A(p.Gly394Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000436 in 1,538,090 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 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000042 (0 hom.)
• Consequence: ITPK1 NM_014216.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.735

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=0.041752815).
• BP6: Variant 14-92941626-C-T is Benign according to our data. Variant chr14-92941626-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3111686.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.1180G>A	p.Gly394Ser	missense_variant	11/11	ENST00000267615.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPK1	ENST00000267615.11	c.1180G>A	p.Gly394Ser	missense_variant	11/11	1	NM_014216.6	P1
ITPK1	ENST00000556603.6	c.1180G>A	p.Gly394Ser	missense_variant	11/11	1		P1
ITPK1	ENST00000555495.5	c.823G>A	p.Gly275Ser	missense_variant	9/9	1
ITPK1	ENST00000354313.7	c.902-3100G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000225 AC: 3 AN: 133120 Hom.: 0 AF XY: 0.0000138 AC XY: 1 AN XY: 72702

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000610

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000419 AC: 58 AN: 1385848 Hom.: 0 Cov.: 35 AF XY: 0.0000322 AC XY: 22 AN XY: 683660

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000587

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000844

Gnomad4 SAS exome AF: 0.0000509

Gnomad4 FIN exome AF: 0.0000229

Gnomad4 NFE exome AF: 0.0000427

Gnomad4 OTH exome AF: 0.0000348

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74380

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000491

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 03, 2024

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	0.070
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	5.4
Dann	Benign	0.64
DEOGEN2	Benign	0.077	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.19	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.28	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.50	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.052
MutPred		0.31		Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);.;
MVP		0.043
MPC		0.43
ClinPred		0.020	T
GERP RS		1.9
Varity_R		0.027
gMVP		0.23

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: rs1043699202; hg19: chr14-93407971;