NM_138386.3:c.1375C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138386.3(NAF1):c.1375C>T(p.His459Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000691 in 1,447,248 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 0.00041 ( 0 hom., cov: 21)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

NAF1
NM_138386.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.120710164).

BS2

High AC in GnomAd4 at 58 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NAF1	NM_138386.3 link	c.1375C>T	p.His459Tyr	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>T	p.His459Tyr	missense_variant	Exon 8 of 8	1	NM_138386.3	ENSP00000274054.2	Q96HR8-1
NAF1	ENST00000422287.6 link	c.1034-1892C>T		intron_variant	Intron 7 of 7	1		ENSP00000408963.2	Q96HR8-2
NAF1	ENST00000509434.5 link	c.114+8192C>T		intron_variant	Intron 2 of 2	3		ENSP00000427518.1	D6RIB3
NAF1	ENST00000509884.1 link	n.*113C>T		downstream_gene_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000412

AC:

AN:

140722

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00143

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000218

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

GnomAD2 exomes

AF:

0.0000503

AC:

AN:

159146

AF XY:

0.0000704

show subpopulations

Gnomad AFR exome

AF:

0.000886

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000321

AC:

AN:

1306526

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

644120

show subpopulations

African (AFR)

AF:

0.00122

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:

0.00000196

AC:

AN:

1018860

Other (OTH)

AF:

0.0000772

AC:

AN:

51792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000412

AC:

AN:

140722

Hom.:

Cov.:

AF XY:

0.000367

AC XY:

AN XY:

68118

show subpopulations

African (AFR)

AF:

0.00143

AC:

AN:

38586

American (AMR)

AF:

0.000218

AC:

AN:

13774

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3342

East Asian (EAS)

AF:

0.00

AC:

AN:

4226

South Asian (SAS)

AF:

0.00

AC:

AN:

3878

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8806

Middle Eastern (MID)

AF:

0.00

AC:

AN:

306

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

64964

Other (OTH)

AF:

0.00

AC:

AN:

1960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000453

ExAC

AF:

0.0000266

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1375C>T (p.H459Y) alteration is located in exon 8 (coding exon 8) of the NAF1 gene. This alteration results from a C to T substitution at nucleotide position 1375, causing the histidine (H) at amino acid position 459 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Nov 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 459 of the NAF1 protein (p.His459Tyr). This variant is present in population databases (rs771014519, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with NAF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2043821). 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0087

Eigen

Benign

-0.067

Eigen_PC

Benign

-0.049

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.52

M_CAP

Benign

0.026

MetaRNN

Benign

0.12

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

1.4

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.89

REVEL

Benign

0.088

Sift

Benign

0.040

Sift4G

Benign

1.0

Polyphen

0.99

Vest4

0.31

MVP

0.45

MPC

0.22

ClinPred

0.058

GERP RS

4.2

Varity_R

0.064

gMVP

0.22

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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NM_138386.3:c.1375C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over