chr11-62801631-G-C

Position:

• chr11-62801631-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_006362.5(NXF1):​c.640C>G​(p.Leu214Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00652 in 1,610,830 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (44 hom.)
• Consequence: NXF1 NM_006362.5 missense, splice_region
• Scores: Splicing: ADA: 0.0005218
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.00

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NXF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.007778913).
• BP6: Variant 11-62801631-G-C is Benign according to our data. Variant chr11-62801631-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 773247.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NXF1	NM_006362.5	c.640C>G	p.Leu214Val	missense_variant, splice_region_variant	7/21	ENST00000294172.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NXF1	ENST00000294172.7	c.640C>G	p.Leu214Val	missense_variant, splice_region_variant	7/21	1	NM_006362.5	P1

Frequencies

GnomAD3 genomes AF: 0.00390 AC: 584 AN: 149704 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00291

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00683

Gnomad OTH AF: 0.00532

GnomAD3 exomes AF: 0.00392 AC: 979 AN: 249792 Hom.: 4 AF XY: 0.00413 AC XY: 558 AN XY: 134994

Gnomad AFR exome AF: 0.00163

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000363

Gnomad FIN exome AF: 0.000604

Gnomad NFE exome AF: 0.00655

Gnomad OTH exome AF: 0.00556

GnomAD4 exome AF: 0.00679 AC: 9921 AN: 1461006 Hom.: 44 Cov.: 32 AF XY: 0.00659 AC XY: 4789 AN XY: 726864

Gnomad4 AFR exome AF: 0.00108

Gnomad4 AMR exome AF: 0.00436

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000302

Gnomad4 FIN exome AF: 0.000880

Gnomad4 NFE exome AF: 0.00835

Gnomad4 OTH exome AF: 0.00524

GnomAD4 genome AF: 0.00390 AC: 584 AN: 149824 Hom.: 3 Cov.: 32 AF XY: 0.00337 AC XY: 247 AN XY: 73202

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00290

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000213

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.00683

Gnomad4 OTH AF: 0.00527

Alfa AF: 0.00520 Hom.: 0

Bravo AF: 0.00419

TwinsUK AF: 0.0105 AC: 39

ALSPAC AF: 0.00830 AC: 32

ExAC AF: 0.00375 AC: 455

EpiCase AF: 0.00695

EpiControl AF: 0.00742

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	18
DANN	Benign	0.96
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T;T;.;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0078	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.10	N;N;N;.;.
MutationTaster	Benign	0.84	D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.8	N;N;N;N;.
Sift	Benign	0.22	T;T;T;T;.
Sift4G	Benign	0.15	T;T;T;T;T
Polyphen		0.0, 0.0070	.;B;B;B;B
Vest4		0.13
MVP		0.51
MPC		0.79
ClinPred		0.019	T
GERP RS		0.91
Varity_R		0.13
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00052
dbscSNV1_RF	Benign	0.086
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: rs191516295; hg19: chr11-62569103; COSMIC: COSV53674546; COSMIC: COSV53674546;