rs1064794277

chr17-31232832-G-Achr17-31232832-G-Cchr17-31232832-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 NM_001042492.3(NF1):c.3447G>A(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 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 NM_001042492.3 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 566155
• 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 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 chr17-31232831-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 where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 17-31232832-G-A is Pathogenic according to our data. Variant chr17-31232832-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 420079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31232832-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2019	For these reasons, this variant has been classified as Pathogenic. A different variant (c.3447G>T) giving rise to the same protein effect observed here (p.Met1149Ile) has been determined to be pathogenic (Invitae), indicating that this residue may be critical for protein function.. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has been reported in several individuals affected with neurofibromatosis type 1, being found to be de novo in one case (PMID: 16944272, 27322474). ClinVar contains an entry for this variant (Variation ID: 420079). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with isoleucine at codon 1149 of the NF1 protein (p.Met1149Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Medical Genomics Laboratory, Department of Genetics UAB	Jun 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 24, 2018

This variant is denoted NF1 c.3447G>A at the cDNA level, p.Met1149Ile (M1149I) at the protein level, and results in the change of a Methionine to an Isoleucine (ATG>ATA). This variant was observed as a de novo finding in one individual with a clinical diagnosis of Neurofibromatosis Type 1 and was not identified in greater than 200 normal chromosomes evaluated (Griffiths 2007). NF1 Met1149Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. NF1 Met1149Ile occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider NF1 Met1149Ile to be a likely pathogenic variant. -

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	27
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	0.83	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
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.57
gMVP		0.88

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

Other links and lift over

dbSNP: rs1064794277; hg19: chr17-29559850;