17-31232832-G-T

Position:

• chr17-31232832-G-T

Variant summary

Our verdict is Pathogenic. Variant got 25 ACMG points: 25P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The ENST00000358273.9(NF1):​c.3447G>T​(p.Met1149Ile) 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 Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1149R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NF1 ENST00000358273.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.53

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 25 ACMG points.

• PS1: Transcript ENST00000358273.9 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 420079
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 15 uncertain in ENST00000358273.9
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31232831-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 660819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 17-31232832-G-T is Pathogenic according to our data. Variant chr17-31232832-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 457650.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31232832-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3447G>T	p.Met1149Ile	missense_variant	26/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3447G>T	p.Met1149Ile	missense_variant	26/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3447G>T	p.Met1149Ile	missense_variant	26/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 26, 2023	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 457650). This missense change has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 16944272, 27322474; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1149 of the NF1 protein (p.Met1149Ile). -
Pathogenic, criteria provided, single submitter	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	Jun 05, 2019	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 12, 2022	Missense variants at residue Met1149, including two other substitutions leading to p.Met1149Ile (c.3447G>A and c.3447G>C), are associated with reduced risk of NF1-associated tumors and increased occurrence of Noonan syndrome-related features (Koczkowska et al., 2020); Reported to segregate with unspecified NF1-associated features in a family (Koczkowska et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25486365, 2121369, 22807134, 29290338, 34928431, 31595648) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 08, 2020	The NF1 c.3447G>T; p.Met1149Ile variant (rs1064794277) is reported in the literature in two individuals affected with neurofibromatosis type 1 (NF1) (Koczkowska 2020). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 1149 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Two other variants leading to the same p.Met1149Ile amino acid substitution (c.3447G>A and c.3447G>C) have been reported in multiple individuals affected with NF1 (Evans 2016, Griffiths 2007, Koczkowska 2020), including a de novo occurrence of the c.3447G>A variant (Griffiths 2007). Further, other missense variants at the same codon (p.Met1149Leu, p.Met1149Thr, p.Met1149Val) have been reported in individuals affected with NF1 and are also considered disease-causing (Koczkowska 2020). Based on available information, the c.3447G>T; p.Met1149Ile variant is considered to be pathogenic. References: Evans DG et al. Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only. EBioMedicine. 2016 May;7:212-20. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Koczkowska M et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat. 2020 Jan;41(1):299-315. -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0050	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.96	D;P;.
Vest4		0.88
MutPred		0.81		Loss of catalytic residue at M1149 (P = 0.005);Loss of catalytic residue at M1149 (P = 0.005);.;
MVP		0.91
MPC		1.4
ClinPred		0.97	D
GERP RS		5.5
Varity_R		0.57
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs1064794277; hg19: chr17-29559850;