Genetic Variant NAP1L2:p.Tyr186Asn (chrX-73213937-A-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_021963.4(NAP1L2):c.556T>A(p.Tyr186Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,208,692 control chromosomes in the GnomAD database, including 1 homozygotes. There are 90 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y186C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00023 ( 1 hom. 85 hem. )

Consequence

NAP1L2
NM_021963.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.355

Variant links:

Genes affected

NAP1L2 (HGNC:7638): (nucleosome assembly protein 1 like 2) The protein encoded by this intronless gene is a member of the nucleosome assembly protein (NAP) family. The encoded protein represents a class of tissue-specific factors that interact with chromatin to regulate neuronal cell proliferation. [provided by RefSeq, Jan 2011]

NAP1L2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025869906).

BS2

High Hemizygotes in GnomAd4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L2	NM_021963.4 link	c.556T>A	p.Tyr186Asn	missense_variant	Exon 1 of 1	ENST00000373517.4	NP_068798.1	Q9ULW6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAP1L2	ENST00000373517.4 link	c.556T>A	p.Tyr186Asn	missense_variant	Exon 1 of 1	6	NM_021963.4	ENSP00000362616.3		Q9ULW6-1

Frequencies

GnomAD3 genomes

AF:

0.000154

AC:

AN:

110636

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

32846

show subpopulations

Gnomad AFR

AF:

0.0000329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000386

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000227

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000224

AC:

AN:

183253

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

67753

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000474

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000306

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.000229

AC:

251

AN:

1098056

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

363414

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000398

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000257

Gnomad4 OTH exome

AF:

0.000412

GnomAD4 genome

AF:

0.000154

AC:

AN:

110636

Hom.:

Cov.:

AF XY:

0.000152

AC XY:

AN XY:

32846

show subpopulations

Gnomad4 AFR

AF:

0.0000329

Gnomad4 AMR

AF:

0.000386

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000227

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000317

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.556T>A (p.Y186N) alteration is located in exon 1 (coding exon 1) of the NAP1L2 gene. This alteration results from a T to A substitution at nucleotide position 556, causing the tyrosine (Y) at amino acid position 186 to be replaced by an asparagine (N). 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

0.060

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.97

CADD

Benign

DANN

Benign

0.63

DEOGEN2

Benign

0.0094

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.53

M_CAP

Benign

0.0010

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.035

PrimateAI

Benign

0.42

PROVEAN

Benign

0.24

REVEL

Benign

0.022

Sift

Benign

0.51

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.12

MutPred

0.40

Loss of phosphorylation at Y186 (P = 0.0174);

MVP

0.043

MPC

0.33

ClinPred

0.021

GERP RS

-2.4

Varity_R

0.047

gMVP

0.29

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over