4-163128946-G-A

Position:

chr4-163128946-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138386.3(NAF1):c.1436C>T(p.Pro479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000134 in 149,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 22)

Exomes 𝑓: 0.0000037 ( 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: 3.14

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 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=0.1514332).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAF1	NM_138386.3 linkuse as main transcript	c.1436C>T	p.Pro479Leu	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.1436C>T	p.Pro479Leu	missense_variant	8/8	1	NM_138386.3	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6 linkuse as main transcript	c.1034-1831C>T		intron_variant		1		ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000509434.5 linkuse as main transcript	c.114+8253C>T		intron_variant		3		ENSP00000427518.1	D6RIB3

Frequencies

GnomAD3 genomes

AF:

0.0000134

AC:

AN:

149236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000498

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:

0.00000472

AC:

AN:

211794

Hom.:

AF XY:

0.00000883

AC XY:

AN XY:

113254

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:

0.00

Gnomad OTH exome

AF:

0.000193

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000366

AC:

AN:

1366064

Hom.:

Cov.:

AF XY:

0.00000590

AC XY:

AN XY:

678068

show subpopulations

Gnomad4 AFR exome

AF:

0.0000629

Gnomad4 AMR exome

AF:

0.0000467

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:

0.00

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.0000134

AC:

AN:

149236

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72728

show subpopulations

Gnomad4 AFR

AF:

0.0000498

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:

0.0000843

Hom.:

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

Dec 12, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with NAF1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 479 of the NAF1 protein (p.Pro479Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.11

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.59

M_CAP

Benign

0.019

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.037

Sift

Benign

0.12

Sift4G

Uncertain

0.016

Polyphen

0.053

Vest4

0.29

MutPred

0.18

Loss of glycosylation at P474 (P = 5e-04);

MVP

0.55

MPC

0.084

ClinPred

0.51

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.055

gMVP

0.19

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