X-93671935-C-G

Variant names:

• chrX-93671935-C-G
• rs752226566
• NM_004538.6:c.1370G>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.1370G>C​(p.Arg457Pro) 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: NAP1L3 NM_004538.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.452

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=0.098582745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAP1L3	NM_004538.6	c.1370G>C	p.Arg457Pro	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.1370G>C	p.Arg457Pro	missense_variant	Exon 1 of 1	6	NM_004538.6	ENSP00000362171.3
NAP1L3	ENST00000475430.2	c.1349G>C	p.Arg450Pro	missense_variant	Exon 2 of 2	2		ENSP00000476891.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.12e-7 AC: 1 AN: 1097029 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362427

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: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1370G>C (p.R457P) alteration is located in exon 1 (coding exon 1) of the NAP1L3 gene. This alteration results from a G to C substitution at nucleotide position 1370, causing the arginine (R) at amino acid position 457 to be replaced by a proline (P). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.0
DANN	Benign	0.84
DEOGEN2	Benign	0.0071	T;T
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.28	T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.42	N;.
REVEL	Benign	0.022
Sift	Benign	0.039	D;.
Sift4G	Benign	0.12	T;T
Polyphen		0.0010	B;.
Vest4		0.16
MutPred		0.46		Loss of helix (P = 0.0093);.;
MVP		0.68
MPC		0.32
ClinPred		0.054	T
GERP RS		-2.5
Varity_R		0.26
gMVP		0.65

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

Other links and lift over

dbSNP: rs752226566; hg19: chrX-92926934;