6-28260564-A-G

Variant names:

• chr6-28260564-A-G
• rs1679709
• NM_001007531.3:c.1193A>G

Variant summary

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

The NM_001007531.3(NKAPL):​c.1193A>G​(p.Glu398Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.851 in 1,611,106 control chromosomes in the GnomAD database, including 585,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.83 (53275 hom., cov: 30)
  • Exomes 𝑓: 0.85 (531883 hom.)
• Consequence: NKAPL NM_001007531.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.53

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=5.3907627E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKAPL	NM_001007531.3	c.1193A>G	p.Glu398Gly	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.1193A>G	p.Glu398Gly	missense_variant	Exon 1 of 1	6	NM_001007531.3	ENSP00000345716.3

Frequencies

GnomAD3 genomes AF: 0.835 AC: 126730 AN: 151856 Hom.: 53228 Cov.: 30

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.857

Gnomad ASJ AF: 0.919

Gnomad EAS AF: 0.879

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.933

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.860

Gnomad OTH AF: 0.853

GnomAD3 exomes AF: 0.872 AC: 217531 AN: 249500 Hom.: 95091 AF XY: 0.875 AC XY: 118094 AN XY: 134910

Gnomad AFR exome AF: 0.731

Gnomad AMR exome AF: 0.876

Gnomad ASJ exome AF: 0.918

Gnomad EAS exome AF: 0.877

Gnomad SAS exome AF: 0.907

Gnomad FIN exome AF: 0.928

Gnomad NFE exome AF: 0.865

Gnomad OTH exome AF: 0.884

GnomAD4 exome AF: 0.853 AC: 1244493 AN: 1459132 Hom.: 531883 Cov.: 37 AF XY: 0.856 AC XY: 621042 AN XY: 725928

Gnomad4 AFR exome AF: 0.728

Gnomad4 AMR exome AF: 0.877

Gnomad4 ASJ exome AF: 0.918

Gnomad4 EAS exome AF: 0.849

Gnomad4 SAS exome AF: 0.908

Gnomad4 FIN exome AF: 0.927

Gnomad4 NFE exome AF: 0.846

Gnomad4 OTH exome AF: 0.861

GnomAD4 genome AF: 0.835 AC: 126832 AN: 151974 Hom.: 53275 Cov.: 30 AF XY: 0.841 AC XY: 62511 AN XY: 74302

Gnomad4 AFR AF: 0.735

Gnomad4 AMR AF: 0.857

Gnomad4 ASJ AF: 0.919

Gnomad4 EAS AF: 0.879

Gnomad4 SAS AF: 0.910

Gnomad4 FIN AF: 0.933

Gnomad4 NFE AF: 0.860

Gnomad4 OTH AF: 0.855

Alfa AF: 0.860 Hom.: 123633

Bravo AF: 0.821

TwinsUK AF: 0.825 AC: 3059

ALSPAC AF: 0.837 AC: 3227

ESP6500AA AF: 0.742 AC: 3268

ESP6500EA AF: 0.860 AC: 7393

ExAC AF: 0.870 AC: 105654

Asia WGS AF: 0.895 AC: 3110 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	20
DANN	Benign	0.82
DEOGEN2	Benign	0.00039	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	5.4e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.021
MPC		0.51
ClinPred		0.0078	T
GERP RS		4.6
Varity_R		0.12
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1679709; hg19: chr6-28228342; COSMIC: COSV59198129;