4-163128904-T-G

Position:

• chr4-163128904-T-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_138386.3(NAF1):​c.1478A>C​(p.Tyr493Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,491,242 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 25)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: NAF1 NM_138386.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.02

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010709286).
• BP6: Variant 4-163128904-T-G is Benign according to our data. Variant chr4-163128904-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1337037.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 202 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NAF1	NM_138386.3	c.1478A>C	p.Tyr493Ser	missense_variant	8/8	ENST00000274054.3	NP_612395.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NAF1	ENST00000274054.3	c.1478A>C	p.Tyr493Ser	missense_variant	8/8	1	NM_138386.3	ENSP00000274054.2
NAF1	ENST00000422287.6	c.1034-1789A>C		intron_variant		1		ENSP00000408963.2
NAF1	ENST00000509434.5	c.114+8295A>C		intron_variant		3		ENSP00000427518.1

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 202 AN: 129366 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00507

Gnomad ASJ AF: 0.00118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00119

Gnomad FIN AF: 0.000169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00226

GnomAD3 exomes AF: 0.00146 AC: 268 AN: 184078 Hom.: 0 AF XY: 0.00164 AC XY: 160 AN XY: 97468

Gnomad AFR exome AF: 0.000414

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.000721

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00112

Gnomad FIN exome AF: 0.000178

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00189

GnomAD4 exome AF: 0.00182 AC: 2474 AN: 1361880 Hom.: 7 Cov.: 31 AF XY: 0.00184 AC XY: 1229 AN XY: 666924

Gnomad4 AFR exome AF: 0.000392

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.000837

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.000429

Gnomad4 NFE exome AF: 0.00205

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.00156 AC: 202 AN: 129362 Hom.: 0 Cov.: 25 AF XY: 0.00159 AC XY: 96 AN XY: 60412

Gnomad4 AFR AF: 0.000269

Gnomad4 AMR AF: 0.00507

Gnomad4 ASJ AF: 0.00118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00120

Gnomad4 FIN AF: 0.000169

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00226

Alfa AF: 0.00167 Hom.: 0

Bravo AF: 0.00129

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000943 AC: 8

ExAC AF: 0.00132 AC: 159

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	NAF1: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 01, 2023	BP4 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 01, 2021

- -

NAF1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 02, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.61
MVP		0.82
MPC		0.54
ClinPred		0.046	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs143001503; hg19: chr4-164050056;