11-62802181-A-G

Position:

• chr11-62802181-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006362.5(NXF1):​c.449T>C​(p.Ile150Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000547 in 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NXF1 NM_006362.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74

Genes affected

NXF1 (HGNC:8071): (nuclear RNA export factor 1) This gene is one member of a family of nuclear RNA export factor genes. Common domain features of this family are a noncanonical RNP-type RNA-binding domain (RBD), 4 leucine-rich repeats (LRRs), a nuclear transport factor 2 (NTF2)-like domain that allows heterodimerization with NTF2-related export protein-1 (NXT1), and a ubiquitin-associated domain that mediates interactions with nucleoporins. The LRRs and NTF2-like domains are required for export activity. Alternative splicing seems to be a common mechanism in this gene family. The encoded protein of this gene shuttles between the nucleus and the cytoplasm and binds in vivo to poly(A)+ RNA. It is the vertebrate homologue of the yeast protein Mex67p. The encoded protein overcomes the mRNA export block caused by the presence of saturating amounts of CTE (constitutive transport element) RNA of type D retroviruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

NXF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NXF1	NM_006362.5	c.449T>C	p.Ile150Thr	missense_variant	4/21	ENST00000294172.7	NP_006353.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NXF1	ENST00000294172.7	c.449T>C	p.Ile150Thr	missense_variant	4/21	1	NM_006362.5	ENSP00000294172.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461798 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.449T>C (p.I150T) alteration is located in exon 4 (coding exon 4) of the NXF1 gene. This alteration results from a T to C substitution at nucleotide position 449, causing the isoleucine (I) at amino acid position 150 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	.;T;T;.;T;T
Eigen	Benign	-0.025
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;T;.;T;D;T
M_CAP	Benign	0.0090	T
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L;L;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.1	D;D;D;D;.;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D;D;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;.
Polyphen		0.022, 0.010, 0.38	.;B;B;B;B;.
Vest4		0.65
MutPred		0.69		Gain of glycosylation at I150 (P = 0.0238);Gain of glycosylation at I150 (P = 0.0238);Gain of glycosylation at I150 (P = 0.0238);.;.;.;
MVP		0.61
MPC		1.0
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.55
gMVP		0.64

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

LitVar

Other links and lift over

dbSNP: rs201574995; hg19: chr11-62569653;