Genetic Variant NCBP3:p.Leu335Gln (chr17-3818569-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001114118.3(NCBP3):c.1004T>A(p.Leu335Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000972 in 1,440,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

NCBP3
NM_001114118.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.37

Variant links:

Genes affected

NCBP3 (HGNC:24612): (nuclear cap binding subunit 3) Enables RNA 7-methylguanosine cap binding activity and mRNA binding activity. Involved in defense response to virus. Located in cytoplasm and nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

NCBP3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.751

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCBP3	NM_001114118.3 link	c.1004T>A	p.Leu335Gln	missense_variant	Exon 10 of 13	ENST00000389005.6	NP_001107590.1	Q53F19-1
NCBP3	NM_001398494.1 link	c.1004T>A	p.Leu335Gln	missense_variant	Exon 10 of 14		NP_001385423.1
NCBP3	XR_007065313.1 link	n.1027T>A		non_coding_transcript_exon_variant	Exon 10 of 15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCBP3	ENST00000389005.6 link	c.1004T>A	p.Leu335Gln	missense_variant	Exon 10 of 13	5	NM_001114118.3	ENSP00000373657.4		Q53F19-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000845

AC:

AN:

236578

Hom.:

AF XY:

0.0000155

AC XY:

AN XY:

128804

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:

0.0000686

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000972

AC:

AN:

1440606

Hom.:

Cov.:

AF XY:

0.0000168

AC XY:

AN XY:

715790

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:

0.000153

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1004T>A (p.L335Q) alteration is located in exon 10 (coding exon 10) of the NCBP3 gene. This alteration results from a T to A substitution at nucleotide position 1004, causing the leucine (L) at amino acid position 335 to be replaced by a glutamine (Q). 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

0.92

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.014

MetaRNN

Pathogenic

0.75

MetaSVM

Benign

-0.42

PROVEAN

Benign

0.10

REVEL

Uncertain

0.34

Sift

Uncertain

0.0010

Sift4G

Benign

0.32

Polyphen

1.0

Vest4

0.95

MutPred

0.24

Loss of stability (P = 0.0331);

MVP

0.21

MPC

1.7

ClinPred

0.69

GERP RS

5.8

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.50

gMVP

0.85

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