NM_012345.3:c.843G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_012345.3(NUFIP1):​c.843G>A​(p.Met281Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,455,442 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M281L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

NUFIP1
NM_012345.3 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03
Variant links:
Genes affected
NUFIP1 (HGNC:8057): (nuclear FMR1 interacting protein 1) This gene encodes a nuclear RNA binding protein that contains a C2H2 zinc finger motif and a nuclear localization signal. This protein is associated with the nuclear matrix in perichromatin fibrils and, in neurons, localizes to the cytoplasm in association with endoplasmic reticulum ribosomes. This protein interacts with the fragile X mental retardation protein (FMRP), the tumor suppressor protein BRCA1, upregulates RNA polymerase II transcription, and is involved in box C/D snoRNP biogenesis. A pseudogene of this gene resides on chromosome 6q12. [provided by RefSeq, Feb 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3993238).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NUFIP1NM_012345.3 linkc.843G>A p.Met281Ile missense_variant Exon 7 of 10 ENST00000379161.5 NP_036477.2 Q9UHK0
NUFIP1XR_941559.3 linkn.878G>A non_coding_transcript_exon_variant Exon 7 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NUFIP1ENST00000379161.5 linkc.843G>A p.Met281Ile missense_variant Exon 7 of 10 1 NM_012345.3 ENSP00000368459.4 Q9UHK0

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000245
AC:
6
AN:
244754
Hom.:
0
AF XY:
0.0000379
AC XY:
5
AN XY:
132028
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000106
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000268
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000117
AC:
17
AN:
1455442
Hom.:
1
Cov.:
31
AF XY:
0.0000180
AC XY:
13
AN XY:
723484
show subpopulations
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:
0.0000830
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000811
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000508
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.0000247
AC:
3
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 03, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.843G>A (p.M281I) alteration is located in exon 7 (coding exon 7) of the NUFIP1 gene. This alteration results from a G to A substitution at nucleotide position 843, causing the methionine (M) at amino acid position 281 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
Pathogenic
0.77
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Benign
-0.31
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.22
T
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.54
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.60
T
M_CAP
Benign
0.022
T
MetaRNN
Benign
0.40
T
MetaSVM
Benign
-0.81
T
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-1.9
N
REVEL
Benign
0.17
Sift
Benign
0.30
T
Sift4G
Uncertain
0.055
T
Polyphen
0.98
D
Vest4
0.48
MutPred
0.41
Gain of catalytic residue at K277 (P = 0.003);
MVP
0.73
MPC
0.33
ClinPred
0.67
D
GERP RS
5.1
Varity_R
0.26
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764426399; hg19: chr13-45533694; API