chr20-1455004-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_016143.5(NSFL1C):​c.407G>A​(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00011 ( 1 hom. )

Consequence

NSFL1C
NM_016143.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.48
Variant links:
Genes affected
NSFL1C (HGNC:15912): (NSFL1 cofactor) N-ethylmaleimide-sensitive factor (NSF) and valosin-containing protein (p97) are two ATPases known to be involved in transport vesicle/target membrane fusion and fusions between membrane compartments. A trimer of the protein encoded by this gene binds a hexamer of cytosolic p97 and is required for p97-mediated regrowth of Golgi cisternae from mitotic Golgi fragments. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 8. [provided by RefSeq, May 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0093584955).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NSFL1CNM_016143.5 linkc.407G>A p.Arg136Gln missense_variant Exon 4 of 9 ENST00000216879.9 NP_057227.2 Q9UNZ2-1Q53FE8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NSFL1CENST00000216879.9 linkc.407G>A p.Arg136Gln missense_variant Exon 4 of 9 1 NM_016143.5 ENSP00000216879.4 Q9UNZ2-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152192
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00248
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000207
AC:
52
AN:
251436
Hom.:
0
AF XY:
0.000280
AC XY:
38
AN XY:
135892
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:
0.00163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000105
AC:
154
AN:
1461746
Hom.:
1
Cov.:
31
AF XY:
0.000153
AC XY:
111
AN XY:
727186
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:
0.00162
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000809
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000985
AC:
15
AN:
152310
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00249
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.0000113
ExAC
AF:
0.000198
AC:
24
Asia WGS
AF:
0.000866
AC:
3
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 05, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.413G>A (p.R138Q) alteration is located in exon 5 (coding exon 5) of the NSFL1C gene. This alteration results from a G to A substitution at nucleotide position 413, causing the arginine (R) at amino acid position 138 to be replaced by a glutamine (Q). 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
0.097
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.017
.;.;T
Eigen
Benign
0.056
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.90
D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.0094
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;.;L
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.41
N;N;N
REVEL
Benign
0.048
Sift
Benign
0.13
T;D;T
Sift4G
Benign
0.47
T;T;T
Polyphen
0.013
B;.;D
Vest4
0.17
MutPred
0.26
Loss of MoRF binding (P = 0.0397);.;Loss of MoRF binding (P = 0.0397);
MVP
0.50
MPC
0.52
ClinPred
0.089
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.064
gMVP
0.36

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

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

Other links and lift over

dbSNP: rs572522929; hg19: chr20-1435649; COSMIC: COSV53793376; COSMIC: COSV53793376; API