9-137449928-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001130969.3(NSMF):​c.1414G>A​(p.Glu472Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NSMF
NM_001130969.3 missense

Scores

1
11
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.86
Variant links:
Genes affected
NSMF (HGNC:29843): (NMDA receptor synaptonuclear signaling and neuronal migration factor) The protein encoded by this gene is involved in guidance of olfactory axon projections and migration of luteinizing hormone-releasing hormone neurons. Defects in this gene are a cause of idiopathic hypogonadotropic hypogonadism (IHH). Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2010]
MIR7114 (HGNC:50157): (microRNA 7114) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.757

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NSMFNM_001130969.3 linkc.1414G>A p.Glu472Lys missense_variant Exon 14 of 16 ENST00000371475.9 NP_001124441.1 Q6X4W1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NSMFENST00000371475.9 linkc.1414G>A p.Glu472Lys missense_variant Exon 14 of 16 1 NM_001130969.3 ENSP00000360530.3 Q6X4W1-1
NSMFENST00000371472.6 linkc.1408G>A p.Glu470Lys missense_variant Exon 13 of 16 2 ENSP00000360527.1 Q6X4W1-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000370
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Apr 03, 2017
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The E470K variant in the NSMF gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E470K variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E470K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret E470K as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Uncertain
0.054
T
BayesDel_noAF
Benign
-0.16
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
.;.;.;.;T;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.43
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D;D;D;.;D;D
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.76
D;D;D;D;D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
1.0
.;.;.;.;L;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
-1.4
N;N;N;N;N;N
REVEL
Benign
0.20
Sift
Uncertain
0.028
D;D;D;D;D;D
Sift4G
Uncertain
0.017
D;D;D;D;D;D
Polyphen
0.66
P;.;P;P;P;P
Vest4
0.76
MutPred
0.34
.;.;.;.;Gain of MoRF binding (P = 0.0105);.;
MVP
0.57
MPC
1.4
ClinPred
0.85
D
GERP RS
4.5
Varity_R
0.33
gMVP
0.91

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: rs1085307813; hg19: chr9-140344380; API