Genetic Variant NAF1:p.His459Asn (chr4-163129007-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138386.3(NAF1):c.1375C>A(p.His459Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,306,526 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H459Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 21)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

NAF1
NM_138386.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.45

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: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NAF1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25883853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAF1	NM_138386.3 link	c.1375C>A	p.His459Asn	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.1375C>A	p.His459Asn	missense_variant	Exon 8 of 8	1	NM_138386.3	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6 link	c.1034-1892C>A		intron_variant	Intron 7 of 7	1		ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000509434.5 link	c.114+8192C>A		intron_variant	Intron 2 of 2	3		ENSP00000427518.1	D6RIB3
NAF1	ENST00000509884.1 link	n.*113C>A		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.65e-7

AC:

AN:

1306526

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

644120

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29578

American (AMR)

AF:

0.00

AC:

AN:

33790

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21860

East Asian (EAS)

AF:

0.00

AC:

AN:

27916

South Asian (SAS)

AF:

0.00

AC:

AN:

79138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39874

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3718

European-Non Finnish (NFE)

AF:

9.81e-7

AC:

AN:

1018860

Other (OTH)

AF:

0.00

AC:

AN:

51792

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.010

Eigen

Benign

0.14

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.50

M_CAP

Benign

0.041

MetaRNN

Benign

0.26

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.1

REVEL

Benign

0.037

Sift

Uncertain

0.011

Sift4G

Benign

0.36

Polyphen

0.98

Vest4

0.22

MutPred

0.19

Loss of glycosylation at P454 (P = 0.1569);

MVP

0.52

MPC

0.091

ClinPred

0.70

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.14

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

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4-163129007-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over