chr17-31249063-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2

The NM_001042492.3(NF1):​c.4054A>T​(p.Ser1352Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. S1352T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NF1
NM_001042492.3 missense

Scores

3
12
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.67
Variant links:
Genes affected
NF1 (HGNC:7765): (neurofibromin 1) This gene product appears to function as a negative regulator of the ras signal transduction pathway. Mutations in this gene have been linked to neurofibromatosis type 1, juvenile myelomonocytic leukemia and Watson syndrome. The mRNA for this gene is subject to RNA editing (CGA>UGA->Arg1306Term) resulting in premature translation termination. Alternatively spliced transcript variants encoding different isoforms have also been described for this gene. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a domain Ras-GAP (size 216) in uniprot entity NF1_HUMAN there are 121 pathogenic changes around while only 10 benign (92%) in NM_001042492.3
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NF1NM_001042492.3 linkuse as main transcriptc.4054A>T p.Ser1352Cys missense_variant 30/58 ENST00000358273.9
NF1NM_000267.3 linkuse as main transcriptc.4054A>T p.Ser1352Cys missense_variant 30/57

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NF1ENST00000358273.9 linkuse as main transcriptc.4054A>T p.Ser1352Cys missense_variant 30/581 NM_001042492.3 P1P21359-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 13, 2023This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1352 of the NF1 protein (p.Ser1352Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 457676). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 10, 2022The p.S1352C variant (also known as c.4054A>T), located in coding exon 30 of the NF1 gene, results from an A to T substitution at nucleotide position 4054. The serine at codon 1352 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Uncertain
0.070
D
BayesDel_noAF
Benign
-0.14
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;.;D
Eigen
Uncertain
0.65
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Benign
0.72
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.62
D
MetaRNN
Uncertain
0.67
D;D;D
MetaSVM
Uncertain
0.41
D
MutationAssessor
Uncertain
2.2
M;M;.
MutationTaster
Benign
0.99
D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Uncertain
-3.4
D;D;D
REVEL
Pathogenic
0.67
Sift
Uncertain
0.0040
D;D;D
Sift4G
Uncertain
0.011
D;D;D
Polyphen
0.94
P;P;.
Vest4
0.46
MutPred
0.55
Loss of disorder (P = 0.0182);Loss of disorder (P = 0.0182);.;
MVP
0.76
MPC
1.1
ClinPred
0.96
D
GERP RS
5.7
Varity_R
0.70
gMVP
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1337343400; hg19: chr17-29576081; API