6-28259545-G-C

Variant summary

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

The NM_001007531.3(NKAPL):c.174G>C(p.Leu58Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKAPL NM_001007531.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.271

Genes affected

NKAPL (HGNC:21584): (NFKB activating protein like) Predicted to enable chromatin binding activity. Predicted to be involved in regulation of gene expression. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.043333054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKAPL	NM_001007531.3	c.174G>C	p.Leu58Phe	missense_variant	1/1	ENST00000343684.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKAPL	ENST00000343684.4	c.174G>C	p.Leu58Phe	missense_variant	1/1		NM_001007531.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2024

The c.174G>C (p.L58F) alteration is located in exon 1 (coding exon 1) of the NKAPL gene. This alteration results from a G to C substitution at nucleotide position 174, causing the leucine (L) at amino acid position 58 to be replaced by a phenylalanine (F). 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	0.079
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	6.2
Dann	Benign	0.94
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.34	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.040
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.056	T
Polyphen		0.0	B
Vest4		0.029
MutPred		0.15		Loss of stability (P = 0.05);
MVP		0.072
MPC		0.47
ClinPred		0.16	T
GERP RS		-1.0
Varity_R		0.050
gMVP		0.054

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr6-28227323;