NM_138386.3:c.1399T>G

Variant names:

• chr4-163128983-A-C
• NM_138386.3:c.1399T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_138386.3(NAF1):​c.1399T>G​(p.Ser467Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0000032 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NAF1 NM_138386.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.821
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09028116).

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.1399T>G	p.Ser467Ala	missense	Exon 8 of 8	NP_612395.2	Q96HR8-1
	NAF1	NM_001128931.2		c.1034-1868T>G		intron	N/A	NP_001122403.1	Q96HR8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NAF1	ENST00000274054.3	TSL:1 MANE Select	c.1399T>G	p.Ser467Ala	missense	Exon 8 of 8	ENSP00000274054.2	Q96HR8-1
	NAF1	ENST00000422287.6	TSL:1	c.1034-1868T>G		intron	N/A	ENSP00000408963.2	Q96HR8-2
	NAF1	ENST00000851282.1		c.1399T>G	p.Ser467Ala	missense	Exon 8 of 9	ENSP00000521341.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000323 AC: 4 AN: 1237030 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 609530

African (AFR) AF: 0.00 AC: 0 AN: 28488

American (AMR) AF: 0.0000286 AC: 1 AN: 34904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19808

East Asian (EAS) AF: 0.00 AC: 0 AN: 24392

South Asian (SAS) AF: 0.00 AC: 0 AN: 78722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3384

European-Non Finnish (NFE) AF: 0.00000312 AC: 3 AN: 962946

Other (OTH) AF: 0.00 AC: 0 AN: 48052

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.0089	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.090	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.82
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.022
Sift	Uncertain	0.020	D
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.18
MutPred		0.16		Loss of glycosylation at P472 (P = 3e-04)
MVP		0.35
MPC		0.40
ClinPred		0.091	T
GERP RS		0.37
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.038
gMVP		0.13
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

hg19: chr4-164050135;