6-28259658-A-G

Position:

• chr6-28259658-A-G

Variant summary

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

The NM_001007531.3(NKAPL):​c.287A>G​(p.Tyr96Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.24 in 1,614,060 control chromosomes in the GnomAD database, including 57,349 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.34 (11185 hom., cov: 33)
  • Exomes 𝑓: 0.23 (46164 hom.)
• Consequence: NKAPL NM_001007531.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.373

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=1.0915858E-5).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NKAPL	NM_001007531.3	c.287A>G	p.Tyr96Cys	missense_variant	1/1	ENST00000343684.4	NP_001007532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NKAPL	ENST00000343684.4	c.287A>G	p.Tyr96Cys	missense_variant	1/1	6	NM_001007531.3	ENSP00000345716.3

Frequencies

GnomAD3 genomes AF: 0.338 AC: 51346 AN: 152104 Hom.: 11132 Cov.: 33

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.177

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.361

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.410

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.376

GnomAD3 exomes AF: 0.284 AC: 71303 AN: 251316 Hom.: 12356 AF XY: 0.281 AC XY: 38123 AN XY: 135844

Gnomad AFR exome AF: 0.607

Gnomad AMR exome AF: 0.331

Gnomad ASJ exome AF: 0.381

Gnomad EAS exome AF: 0.438

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.269

GnomAD4 exome AF: 0.230 AC: 336499 AN: 1461838 Hom.: 46164 Cov.: 37 AF XY: 0.235 AC XY: 170554 AN XY: 727222

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.374

Gnomad4 EAS exome AF: 0.455

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.192

Gnomad4 OTH exome AF: 0.272

GnomAD4 genome AF: 0.338 AC: 51454 AN: 152222 Hom.: 11185 Cov.: 33 AF XY: 0.338 AC XY: 25161 AN XY: 74428

Gnomad4 AFR AF: 0.600

Gnomad4 AMR AF: 0.362

Gnomad4 ASJ AF: 0.361

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.412

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.373

Alfa AF: 0.237 Hom.: 12538

Bravo AF: 0.366

TwinsUK AF: 0.179 AC: 664

ALSPAC AF: 0.183 AC: 707

ESP6500AA AF: 0.580 AC: 2555

ESP6500EA AF: 0.204 AC: 1757

ExAC AF: 0.286 AC: 34677

Asia WGS AF: 0.393 AC: 1363 AN: 3478

EpiCase AF: 0.212

EpiControl AF: 0.213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.9
DANN	Benign	0.75
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.74	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.051
Sift	Benign	0.047	D
Sift4G	Benign	0.17	T
Polyphen		0.0020	B
Vest4		0.055
MPC		0.54
ClinPred		0.0054	T
GERP RS		1.9
Varity_R		0.085
gMVP		0.10

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: rs12000; hg19: chr6-28227436; COSMIC: COSV59197971;