14-92941623-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.1183G>A(p.Val395Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000904 in 1,538,144 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 0.000099 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000089 (0 hom.)
• Consequence: ITPK1 NM_014216.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.41

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=0.067279845).
• BP6: Variant 14-92941623-C-T is Benign according to our data. Variant chr14-92941623-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2371051.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.1183G>A	p.Val395Met	missense_variant	11/11	ENST00000267615.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ITPK1	ENST00000267615.11	c.1183G>A	p.Val395Met	missense_variant	11/11	1	NM_014216.6	P1
ITPK1	ENST00000556603.6	c.1183G>A	p.Val395Met	missense_variant	11/11	1		P1
ITPK1	ENST00000555495.5	c.826G>A	p.Val276Met	missense_variant	9/9	1
ITPK1	ENST00000354313.7	c.902-3097G>A		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152256 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000225 AC: 3 AN: 133150 Hom.: 0 AF XY: 0.0000137 AC XY: 1 AN XY: 72730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000441

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: 0.0000203

Gnomad OTH exome AF: 0.000255

GnomAD4 exome AF: 0.0000895 AC: 124 AN: 1385888 Hom.: 0 Cov.: 35 AF XY: 0.0000702 AC XY: 48 AN XY: 683686

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000294

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000563

Gnomad4 SAS exome AF: 0.0000509

Gnomad4 FIN exome AF: 0.0000915

Gnomad4 NFE exome AF: 0.0000985

Gnomad4 OTH exome AF: 0.000104

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152256 Hom.: 0 Cov.: 34 AF XY: 0.0000941 AC XY: 7 AN XY: 74386

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000299 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000534 AC: 4

Asia WGS AF: 0.000289 AC: 1 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

Jun 21, 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	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Benign	0.38
DEOGEN2	Benign	0.084	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.63	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;N;.
MutationTaster	Benign	0.98	D;N;N;N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.17	N;N;N
REVEL	Benign	0.066
Sift	Benign	0.46	T;T;T
Sift4G	Benign	0.35	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.18
MVP		0.13
MPC		0.44
ClinPred		0.016	T
GERP RS		2.0
Varity_R		0.025
gMVP		0.20

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: rs765232616; hg19: chr14-93407968; COSMIC: COSV99032609; COSMIC: COSV99032609;