rs9461446

Variant names:

• chr6-28259855-C-T
• rs9461446
• NM_001007531.3:c.484C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001007531.3(NKAPL):​c.484C>T​(p.His162Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,613,944 control chromosomes in the GnomAD database, including 2,390 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.053 (263 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2127 hom.)
• Consequence: NKAPL NM_001007531.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.224

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019891262).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKAPL	NM_001007531.3	c.484C>T	p.His162Tyr	missense_variant	Exon 1 of 1	ENST00000343684.4	NP_001007532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKAPL	ENST00000343684.4	c.484C>T	p.His162Tyr	missense_variant	Exon 1 of 1	6	NM_001007531.3	ENSP00000345716.3

Frequencies

GnomAD3 genomes AF: 0.0533 AC: 8107 AN: 152014 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.0567

Gnomad AMI AF: 0.0198

Gnomad AMR AF: 0.0845

Gnomad ASJ AF: 0.0470

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0839

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0423

Gnomad OTH AF: 0.0641

GnomAD3 exomes AF: 0.0591 AC: 14825 AN: 251006 Hom.: 528 AF XY: 0.0594 AC XY: 8072 AN XY: 135794

Gnomad AFR exome AF: 0.0552

Gnomad AMR exome AF: 0.0857

Gnomad ASJ exome AF: 0.0469

Gnomad EAS exome AF: 0.117

Gnomad SAS exome AF: 0.0859

Gnomad FIN exome AF: 0.0313

Gnomad NFE exome AF: 0.0415

Gnomad OTH exome AF: 0.0539

GnomAD4 exome AF: 0.0482 AC: 70518 AN: 1461812 Hom.: 2127 Cov.: 35 AF XY: 0.0495 AC XY: 35961 AN XY: 727206

Gnomad4 AFR exome AF: 0.0563

Gnomad4 AMR exome AF: 0.0833

Gnomad4 ASJ exome AF: 0.0474

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0851

Gnomad4 FIN exome AF: 0.0307

Gnomad4 NFE exome AF: 0.0410

Gnomad4 OTH exome AF: 0.0487

GnomAD4 genome AF: 0.0533 AC: 8109 AN: 152132 Hom.: 263 Cov.: 32 AF XY: 0.0539 AC XY: 4008 AN XY: 74382

Gnomad4 AFR AF: 0.0565

Gnomad4 AMR AF: 0.0845

Gnomad4 ASJ AF: 0.0470

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.0845

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0423

Gnomad4 OTH AF: 0.0630

Alfa AF: 0.0448 Hom.: 420

Bravo AF: 0.0581

TwinsUK AF: 0.0423 AC: 157

ALSPAC AF: 0.0459 AC: 177

ESP6500AA AF: 0.0493 AC: 217

ESP6500EA AF: 0.0435 AC: 374

ExAC AF: 0.0571 AC: 6928

Asia WGS AF: 0.0870 AC: 302 AN: 3478

EpiCase AF: 0.0413

EpiControl AF: 0.0429

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.7
DANN	Benign	0.64
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.013
Sift	Benign	0.034	D
Sift4G	Benign	0.15	T
Polyphen		0.39	B
Vest4		0.044
MPC		0.50
ClinPred		0.000022	T
GERP RS		-1.6
Varity_R		0.050
gMVP		0.017

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs9461446; hg19: chr6-28227633; COSMIC: COSV59199492;