X-93672559-T-G

Variant names:

• chrX-93672559-T-G
• NM_004538.6:c.746A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004538.6(NAP1L3):​c.746A>C​(p.Lys249Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: NAP1L3 NM_004538.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17381808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L3	NM_004538.6	c.746A>C	p.Lys249Thr	missense_variant	Exon 1 of 1	ENST00000373079.4	NP_004529.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NAP1L3	ENST00000373079.4	c.746A>C	p.Lys249Thr	missense_variant	Exon 1 of 1	6	NM_004538.6	ENSP00000362171.3
NAP1L3	ENST00000475430.2	c.725A>C	p.Lys242Thr	missense_variant	Exon 2 of 2	2		ENSP00000476891.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.746A>C (p.K249T) alteration is located in exon 1 (coding exon 1) of the NAP1L3 gene. This alteration results from a A to C substitution at nucleotide position 746, causing the lysine (K) at amino acid position 249 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	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0065	T;T
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.51	N;.
REVEL	Benign	0.041
Sift	Uncertain	0.010	D;.
Sift4G	Benign	0.26	T;T
Polyphen		0.77	P;.
Vest4		0.14
MutPred		0.41		Loss of ubiquitination at K249 (P = 0.0034);.;
MVP		0.48
MPC		0.85
ClinPred		0.77	D
GERP RS		3.3
Varity_R		0.25
gMVP		0.15

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-92927558;