Genetic Variant NAP1L3:p.Gly486Glu (chrX-93671848-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_004538.6(NAP1L3):c.1457G>A(p.Gly486Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,574 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )

Consequence

NAP1L3
NM_004538.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L3	NM_004538.6 link	c.1457G>A	p.Gly486Glu	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.1457G>A	p.Gly486Glu	missense_variant	Exon 1 of 1	6	NM_004538.6	ENSP00000362171.3		Q99457
NAP1L3	ENST00000475430.2 link	c.1436G>A	p.Gly479Glu	missense_variant	Exon 2 of 2	2		ENSP00000476891.1		V9GYL6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000548

AC:

AN:

182442

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

67040

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:

0.0000530

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097574

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

362954

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:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1457G>A (p.G486E) 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 1457, causing the glycine (G) at amino acid position 486 to be replaced by a glutamic acid (E). 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

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.013

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.027

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Benign

-0.35

MutationAssessor

Pathogenic

3.2

M;.

PrimateAI

Benign

0.44

PROVEAN

Pathogenic

-7.6

D;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0030

D;D

Polyphen

0.99

D;.

Vest4

0.69

MutPred

0.88

Gain of relative solvent accessibility (P = 0.09);.;

MVP

0.89

MPC

0.96

ClinPred

0.98

GERP RS

3.4

Varity_R

0.95

gMVP

0.69

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