chr11-62796097-T-A

Position:

• chr11-62796097-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006362.5(NXF1):​c.1430A>T​(p.Asn477Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NXF1 NM_006362.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NXF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.39462006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NXF1	NM_006362.5	c.1430A>T	p.Asn477Ile	missense_variant	16/21	ENST00000294172.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NXF1	ENST00000294172.7	c.1430A>T	p.Asn477Ile	missense_variant	16/21	1	NM_006362.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461408 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727004

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Jun 05, 2023

The c.1430A>T (p.N477I) alteration is located in exon 16 (coding exon 16) of the NXF1 gene. This alteration results from a A to T substitution at nucleotide position 1430, causing the asparagine (N) at amino acid position 477 to be replaced by an isoleucine (I). 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	0.29
BayesDel_addAF	Benign	-0.00087	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;.;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Benign	0.24
Sift	Benign	0.060	T;T;D
Sift4G	Uncertain	0.058	T;T;D
Polyphen		0.92	P;P;B
Vest4		0.72
MutPred		0.50		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.72
MPC		1.0
ClinPred		0.89	D
GERP RS		3.6
Varity_R		0.43
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-62563569;