Variant 4-163129120-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138386.3(NAF1):c.1262A>G(p.Gln421Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,248 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 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

NAF1
NM_138386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16407365).

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAF1	NM_138386.3 link	c.1262A>G	p.Gln421Arg	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 link	c.1262A>G	p.Gln421Arg	missense_variant	8/8	1	NM_138386.3	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6 link	c.1034-2005A>G		intron_variant		1		ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000509434.5 link	c.114+8079A>G		intron_variant		3		ENSP00000427518.1	D6RIB3
NAF1	ENST00000509884.1 link	n.718A>G		splice_region_variant, non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.00000800

AC:

AN:

249984

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135338

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:

0.00000889

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461260

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726970

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000387

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151988

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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

Alfa

AF:

0.0000450

Hom.:

Bravo

AF:

0.0000113

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

Jun 21, 2023

This variant has not been reported in the literature in individuals affected with NAF1-related conditions. 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 is present in population databases (no rsID available, gnomAD 0.008%). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 421 of the NAF1 protein (p.Gln421Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.050

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.67

M_CAP

Benign

0.023

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.1

REVEL

Benign

0.025

Sift

Benign

0.068

Sift4G

Benign

0.40

Polyphen

0.24

Vest4

0.25

MutPred

0.15

Gain of glycosylation at Y422 (P = 0.0685);

MVP

0.72

MPC

0.14

ClinPred

0.072

GERP RS

0.10

Varity_R

0.048

gMVP

0.28

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