Variant 4-163128980-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138386.3(NAF1):c.1402C>G(p.Leu468Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,381,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 21)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NAF1
NM_138386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.258

Variant links:

Genes affected

NAF1 (HGNC:25126): (nuclear assembly factor 1 ribonucleoprotein) Enables identical protein binding activity and telomerase RNA binding activity. Involved in regulation of nucleobase-containing compound metabolic process; ribosome biogenesis; and telomerase holoenzyme complex assembly. Located in nucleoplasm. Part of sno(s)RNA-containing ribonucleoprotein complex. [provided by Alliance of Genome Resources, Apr 2022]

NAF1 links:

NAF1 (HGNC:):

NAF1 links:

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=0.05455631).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAF1	NM_138386.3 linkuse as main transcript	c.1402C>G	p.Leu468Val	missense_variant	8/8	ENST00000274054.3	NP_612395.2	Q96HR8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
NAF1	ENST00000274054.3 linkuse as main transcript	c.1402C>G	p.Leu468Val	missense_variant	8/8	1	NM_138386.3	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6 linkuse as main transcript	c.1034-1865C>G		intron_variant		1		ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000509434.5 linkuse as main transcript	c.114+8219C>G		intron_variant		3		ENSP00000427518.1	D6RIB3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

148400

Hom.:

Cov.:

FAILED QC

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183454

Hom.:

AF XY:

0.00

AC XY:

AN XY:

98182

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:

0.00

Gnomad NFE exome

AF:

0.0000136

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000434

AC:

AN:

1381022

Hom.:

Cov.:

AF XY:

0.00000585

AC XY:

AN XY:

683986

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:

0.00

Gnomad4 NFE exome

AF:

0.00000569

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

148400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72294

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 22, 2023

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 468 of the NAF1 protein (p.Leu468Val). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This variant has not been reported in the literature in individuals affected with NAF1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.78

DANN

Benign

0.60

DEOGEN2

Benign

0.0088

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.45

M_CAP

Benign

0.012

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.23

REVEL

Benign

0.048

Sift

Uncertain

0.023

Sift4G

Benign

0.49

Polyphen

0.096

Vest4

0.14

MutPred

0.13

Loss of glycosylation at P472 (P = 3e-04);

MVP

0.28

MPC

0.10

ClinPred

0.041

GERP RS

-0.078

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.028

gMVP

0.076

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