rs1555615071

Variant names:

• chr17-31233149-T-A
• NM_001042492.3:c.3644T>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31233149-T-A
• chr17-31233149-T-C
• chr17-31233149-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5

The NM_001042492.3(NF1):​c.3644T>A​(p.Met1215Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1215R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 7.64

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a helix (size 8) in uniprot entity NF1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31233149-T-G is described in Lovd as [Pathogenic].
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887
• PP5: Variant 17-31233149-T-A is Pathogenic according to our data. Variant chr17-31233149-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2137980.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=1}. Variant chr17-31233149-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3644T>A	p.Met1215Lys	missense_variant	Exon 27 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3644T>A	p.Met1215Lys	missense_variant	Exon 27 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3644T>A	p.Met1215Lys	missense_variant	Exon 27 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Mar 31, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3644T>A; p.Met1215Lys variant, to our knowledge, is not reported in the medical literature, but is reported in an NF1 specific database as occurring de novo in at least one individual (see link below). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The methionine at codon 1215 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.945). Another variant in the same codon, c.3644T>G; p.Met1215Arg, is reported as occurring de novo in several individuals and is considered pathogenic (see link below, Bianchessi 2015). Additionally, other variants occurring in this codon have been reported in affected individuals (ClinVar Variation IDs: 547631, 1040466). However, given the lack of clinical and functional data, the significance of the p.Met1215Lys variant is uncertain at this time. References: Link to NF1 database: https://databases.lovd.nl/shared/genes/NF1 Bianchessi D et al. 126 novel mutations in Italian patients with neurofibromatosis type 1. Mol Genet Genomic Med. 2015 Jul 7;3(6):513-25. PMID: 26740943. -

Jul 12, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25486365, 22807134, 23656349, 26740943) -

Neurofibromatosis, type 1 Pathogenic:1

Sep 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1215 of the NF1 protein (p.Met1215Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (Invitae). 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. This variant disrupts the p.Met1215 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 26740943). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.81	D;.;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.1	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.016	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.98	D;P;.
Vest4		0.99
MutPred		0.58		Gain of ubiquitination at M1215 (P = 0.0258);Gain of ubiquitination at M1215 (P = 0.0258);.;
MVP		0.97
MPC		1.9
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.97

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29560167;