chr4-163129034-C-T

Variant names:

• chr4-163129034-C-T
• rs200516616
• NM_138386.3:c.1348G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_138386.3(NAF1):​c.1348G>A​(p.Gly450Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00736 in 1,393,560 control chromosomes in the GnomAD database, including 46 homozygotes. 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 20)
  • Exomes 𝑓: 0.0077 (43 hom.)
• Consequence: NAF1 NM_138386.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.233
• Publications: 6 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0061169863).
• BP6: Variant 4-163129034-C-T is Benign according to our data. Variant chr4-163129034-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1336132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 587 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.1348G>A	p.Gly450Ser	missense	Exon 8 of 8	NP_612395.2	Q96HR8-1
	NAF1	NM_001128931.2		c.1034-1919G>A		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.1348G>A	p.Gly450Ser	missense	Exon 8 of 8	ENSP00000274054.2	Q96HR8-1
	NAF1	ENST00000422287.6	TSL:1	c.1034-1919G>A		intron	N/A	ENSP00000408963.2	Q96HR8-2
	NAF1	ENST00000851282.1		c.1348G>A	p.Gly450Ser	missense	Exon 8 of 9	ENSP00000521341.1

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 587 AN: 133440 Hom.: 3 Cov.: 20

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00342

Gnomad ASJ AF: 0.000300

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000275

Gnomad FIN AF: 0.000268

Gnomad MID AF: 0.00333

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.00381

GnomAD2 exomes AF: 0.00389 AC: 581 AN: 149532 AF XY: 0.00388

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.000242

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000896

Gnomad NFE exome AF: 0.00777

Gnomad OTH exome AF: 0.00835

GnomAD4 exome AF: 0.00768 AC: 9674 AN: 1259996 Hom.: 43 Cov.: 30 AF XY: 0.00743 AC XY: 4602 AN XY: 619576

African (AFR) AF: 0.00122 AC: 34 AN: 27958

American (AMR) AF: 0.00448 AC: 143 AN: 31922

Ashkenazi Jewish (ASJ) AF: 0.000144 AC: 3 AN: 20822

East Asian (EAS) AF: 0.00 AC: 0 AN: 27272

South Asian (SAS) AF: 0.0000129 AC: 1 AN: 77306

European-Finnish (FIN) AF: 0.00110 AC: 39 AN: 35334

Middle Eastern (MID) AF: 0.00141 AC: 5 AN: 3556

European-Non Finnish (NFE) AF: 0.00923 AC: 9103 AN: 986452

Other (OTH) AF: 0.00701 AC: 346 AN: 49374

GnomAD4 genome AF: 0.00439 AC: 587 AN: 133564 Hom.: 3 Cov.: 20 AF XY: 0.00400 AC XY: 256 AN XY: 63980

African (AFR) AF: 0.00142 AC: 50 AN: 35306

American (AMR) AF: 0.00341 AC: 44 AN: 12894

Ashkenazi Jewish (ASJ) AF: 0.000300 AC: 1 AN: 3332

East Asian (EAS) AF: 0.00 AC: 0 AN: 4012

South Asian (SAS) AF: 0.000274 AC: 1 AN: 3646

European-Finnish (FIN) AF: 0.000268 AC: 2 AN: 7476

Middle Eastern (MID) AF: 0.00357 AC: 1 AN: 280

European-Non Finnish (NFE) AF: 0.00753 AC: 481 AN: 63896

Other (OTH) AF: 0.00377 AC: 7 AN: 1858

Alfa AF: 0.00621 Hom.: 11

Bravo AF: 0.00461

ESP6500AA AF: 0.000968 AC: 4

ESP6500EA AF: 0.00610 AC: 49

ExAC AF: 0.00181 AC: 176

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	11
DANN	Benign	0.65
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.41	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.23
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.025
Sift	Benign	0.25	T
Sift4G	Benign	0.64	T
Polyphen		0.14	B
Vest4		0.081
MVP		0.30
MPC		0.080
ClinPred		0.0032	T
GERP RS		-0.65
Varity_R		0.029
gMVP		0.16
Mutation Taster		=92/8	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

dbSNP: rs200516616; hg19: chr4-164050186; COSMIC: COSV99066824; COSMIC: COSV99066824;