Genetic Variant NAP1L3:p.Ala437Thr (chrX-93671996-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

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

The NM_004538.6(NAP1L3):c.1309G>A(p.Ala437Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000566 in 1,202,127 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 33 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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. A437G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 7 hem., cov: 22)

Exomes 𝑓: 0.000050 ( 0 hom. 26 hem. )

Consequence

NAP1L3
NM_004538.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.136

Variant links:

Genes affected

NAP1L3 (HGNC:7639): (nucleosome assembly protein 1 like 3) This gene is intronless and encodes a member of the nucleosome assembly protein (NAP) family. This gene is linked closely to a region of genes responsible for several X-linked cognitive disability syndromes. [provided by RefSeq, Dec 2010]

NAP1L3 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=0.05846101).

BS2

High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L3	NM_004538.6 link	c.1309G>A	p.Ala437Thr	missense_variant	Exon 1 of 1	ENST00000373079.4	NP_004529.2	Q99457Q8IYV1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAP1L3	ENST00000373079.4 link	c.1309G>A	p.Ala437Thr	missense_variant	Exon 1 of 1	6	NM_004538.6	ENSP00000362171.3		Q99457
NAP1L3	ENST00000475430.2 link	c.1288G>A	p.Ala430Thr	missense_variant	Exon 2 of 2	2		ENSP00000476891.1		V9GYL6

Frequencies

GnomAD3 genomes

AF:

0.000117

AC:

AN:

111424

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

33586

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000833

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000151

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000840

AC:

AN:

166625

Hom.:

AF XY:

0.000131

AC XY:

AN XY:

53591

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000199

Gnomad NFE exome

AF:

0.000139

Gnomad OTH exome

AF:

0.000236

GnomAD4 exome

AF:

0.0000504

AC:

AN:

1090703

Hom.:

Cov.:

AF XY:

0.0000728

AC XY:

AN XY:

357145

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000299

Gnomad4 NFE exome

AF:

0.0000513

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000117

AC:

AN:

111424

Hom.:

Cov.:

AF XY:

0.000208

AC XY:

AN XY:

33586

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000833

Gnomad4 NFE

AF:

0.000151

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000743

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1309G>A (p.A437T) alteration is located in exon 1 (coding exon 1) of the NAP1L3 gene. This alteration results from a G to A substitution at nucleotide position 1309, causing the alanine (A) at amino acid position 437 to be replaced by a threonine (T). 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

0.15

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.0056

T;T

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.77

T;T

M_CAP

Benign

0.0051

MetaRNN

Benign

0.058

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;.

PrimateAI

Benign

0.32

PROVEAN

Benign

0.36

N;.

REVEL

Benign

0.043

Sift

Uncertain

0.021

D;.

Sift4G

Benign

0.077

T;T

Polyphen

0.017

B;.

Vest4

0.13

MutPred

0.34

Gain of phosphorylation at A437 (P = 0.1001);.;

MVP

0.71

MPC

0.22

ClinPred

0.12

GERP RS

0.60

Varity_R

0.13

gMVP

0.22

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

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