3-23910864-G-T

Variant names:

• chr3-23910864-G-T
• NM_020345.4:c.41C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001377366.1(NKIRAS1):​c.-125C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NKIRAS1 NM_001377366.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

Genes affected

NKIRAS1 (HGNC:17899): (NFKB inhibitor interacting Ras like 1) Predicted to enable GTPase activating protein binding activity. Predicted to be involved in I-kappaB kinase/NF-kappaB signaling. Predicted to act upstream of or within several processes, including Ral protein signal transduction; lung alveolus development; and surfactant homeostasis. Located in cytosol and endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKIRAS1	NM_020345.4	c.41C>A	p.Ser14Tyr	missense_variant	Exon 3 of 5	ENST00000425478.7	NP_065078.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKIRAS1	ENST00000425478.7	c.41C>A	p.Ser14Tyr	missense_variant	Exon 3 of 5	1	NM_020345.4	ENSP00000400385.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41C>A (p.S14Y) alteration is located in exon 3 (coding exon 1) of the NKIRAS1 gene. This alteration results from a C to A substitution at nucleotide position 41, causing the serine (S) at amino acid position 14 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;D;D;D;D;D;D;D;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;.;.;D;.;.;D;.
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	3.1	M;M;M;M;M;.;.;.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	D;D;D;D;.;D;D;D;D
REVEL	Pathogenic	0.75
Sift	Benign	0.039	D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.060	T;T;T;T;T;T;T;T;T
Polyphen		0.83	P;P;P;P;P;P;P;P;P
Vest4		0.56
MutPred		0.62		Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);Loss of ubiquitination at K17 (P = 0.0962);
MVP		0.89
MPC		1.1
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.38
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-23952355;