X-93671996-C-T

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

3
14

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]

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
NAP1L3NM_004538.6 linkc.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
NAP1L3ENST00000373079.4 linkc.1309G>A p.Ala437Thr missense_variant Exon 1 of 1 6 NM_004538.6 ENSP00000362171.3 Q99457
NAP1L3ENST00000475430.2 linkc.1288G>A p.Ala430Thr missense_variant Exon 2 of 2 2 ENSP00000476891.1 V9GYL6

Frequencies

GnomAD3 genomes
AF:
0.000117
AC:
13
AN:
111424
Hom.:
0
Cov.:
22
AF XY:
0.000208
AC XY:
7
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:
14
AN:
166625
Hom.:
0
AF XY:
0.000131
AC XY:
7
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:
55
AN:
1090703
Hom.:
0
Cov.:
31
AF XY:
0.0000728
AC XY:
26
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:
13
AN:
111424
Hom.:
0
Cov.:
22
AF XY:
0.000208
AC XY:
7
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.:
1
Bravo
AF:
0.0000680
ExAC
AF:
0.0000743
AC:
9

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
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
12
DANN
Benign
0.95
DEOGEN2
Benign
0.0056
T;T
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.058
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.5
M;.
PrimateAI
Benign
0.32
T
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
T
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.

Other links and lift over

dbSNP: rs745639264; hg19: chrX-92926995; API