4-163128904-T-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_138386.3(NAF1):c.1478A>C(p.Tyr493Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,491,242 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0016 ( 0 hom., cov: 25)

Exomes 𝑓: 0.0018 ( 7 hom. )

Consequence

NAF1
NM_138386.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010709286).

BP6

Variant 4-163128904-T-G is Benign according to our data. Variant chr4-163128904-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1337037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAF1	NM_138386.3 link	c.1478A>C	p.Tyr493Ser	missense_variant	Exon 8 of 8	ENST00000274054.3	NP_612395.2	Q96HR8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NAF1	ENST00000274054.3 link	c.1478A>C	p.Tyr493Ser	missense_variant	Exon 8 of 8	1	NM_138386.3	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6 link	c.1034-1789A>C		intron_variant	Intron 7 of 7	1		ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000509434.5 link	c.114+8295A>C		intron_variant	Intron 2 of 2	3		ENSP00000427518.1	D6RIB3
NAF1	ENST00000509884.1 link	n.*216A>C		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00156

AC:

202

AN:

129366

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00507

Gnomad ASJ

AF:

0.00118

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00119

Gnomad FIN

AF:

0.000169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00226

GnomAD3 exomes

AF:

0.00146

AC:

268

AN:

184078

Hom.:

AF XY:

0.00164

AC XY:

160

AN XY:

97468

show subpopulations

Gnomad AFR exome

AF:

0.000414

Gnomad AMR exome

AF:

0.00197

Gnomad ASJ exome

AF:

0.000721

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00112

Gnomad FIN exome

AF:

0.000178

Gnomad NFE exome

AF:

0.00208

Gnomad OTH exome

AF:

0.00189

GnomAD4 exome

AF:

0.00182

AC:

2474

AN:

1361880

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1229

AN XY:

666924

show subpopulations

Gnomad4 AFR exome

AF:

0.000392

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.000837

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00133

Gnomad4 FIN exome

AF:

0.000429

Gnomad4 NFE exome

AF:

0.00205

Gnomad4 OTH exome

AF:

0.00143

GnomAD4 genome

AF:

0.00156

AC:

202

AN:

129362

Hom.:

Cov.:

AF XY:

0.00159

AC XY:

AN XY:

60412

show subpopulations

Gnomad4 AFR

AF:

0.000269

Gnomad4 AMR

AF:

0.00507

Gnomad4 ASJ

AF:

0.00118

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00120

Gnomad4 FIN

AF:

0.000169

Gnomad4 NFE

AF:

0.00197

Gnomad4 OTH

AF:

0.00226

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.00129

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000943

AC:

ExAC

AF:

0.00132

AC:

159

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NAF1: BS1 -

May 01, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

not specified

Benign:1

Dec 01, 2021

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NAF1-related disorder

Benign:1

Apr 02, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.49

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.82

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.83

REVEL

Benign

0.15

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.99

Vest4

0.61

MVP

0.82

MPC

0.54

ClinPred

0.046

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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