dbSNP rs1012073639: NAF1:p.Val447Ile (chr4-163129043-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_138386.3(NAF1):c.1339G>A(p.Val447Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000389 in 1,106,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000060 ( 0 hom., cov: 14)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

NAF1
NM_138386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0730

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

pulmonary fibrosis and/or bone marrow failure syndrome, telomere-related, 7
Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)

NAF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06339535).

BS2

High AC in GnomAdExome4 at 39 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138386.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAF1	NM_138386.3	MANE Select	c.1339G>A	p.Val447Ile	missense	Exon 8 of 8	NP_612395.2	Q96HR8-1
	NAF1	NM_001128931.2		c.1034-1928G>A		intron	N/A	NP_001122403.1	Q96HR8-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NAF1	ENST00000274054.3	TSL:1 MANE Select	c.1339G>A	p.Val447Ile	missense	Exon 8 of 8	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6	TSL:1	c.1034-1928G>A		intron	N/A	ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000851282.1		c.1339G>A	p.Val447Ile	missense	Exon 8 of 9	ENSP00000521341.1

Frequencies

GnomAD3 genomes

AF:

0.0000599

AC:

AN:

66792

Hom.:

Cov.:

show subpopulations

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:

0.000108

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

147510

AF XY:

0.0000125

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000368

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000375

AC:

AN:

1039316

Hom.:

Cov.:

AF XY:

0.0000350

AC XY:

AN XY:

513750

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22322

American (AMR)

AF:

0.00

AC:

AN:

28232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15230

East Asian (EAS)

AF:

0.00

AC:

AN:

12424

South Asian (SAS)

AF:

0.00

AC:

AN:

74024

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27128

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2672

European-Non Finnish (NFE)

AF:

0.0000452

AC:

AN:

819286

Other (OTH)

AF:

0.0000526

AC:

AN:

37998

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000599

AC:

AN:

66792

Hom.:

Cov.:

AF XY:

0.0000992

AC XY:

AN XY:

30230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

16308

American (AMR)

AF:

0.00

AC:

AN:

4158

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1946

East Asian (EAS)

AF:

0.00

AC:

AN:

2232

South Asian (SAS)

AF:

0.00

AC:

AN:

1952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

1738

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.000108

AC:

AN:

37008

Other (OTH)

AF:

0.00

AC:

AN:

838

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000902

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.019

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.48

M_CAP

Benign

0.014

MetaRNN

Benign

0.063

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

-0.073

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.36

REVEL

Benign

0.047

Sift

Benign

0.097

Sift4G

Benign

0.44

Polyphen

0.16

Vest4

0.12

MutPred

0.17

Loss of glycosylation at P443 (P = 3e-04)

MVP

0.33

MPC

0.076

ClinPred

0.067

GERP RS

2.8

Varity_R

0.026

gMVP

0.072

Mutation Taster

=93/7

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over