17-31156044-A-T

Position:

• chr17-31156044-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_001042492.3(NF1):​c.122A>T​(p.Glu41Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.78

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]

NF1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• 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.
• PP5: Variant 17-31156044-A-T is Pathogenic according to our data. Variant chr17-31156044-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 586954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.122A>T	p.Glu41Val	missense_variant	2/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.122A>T	p.Glu41Val	missense_variant	2/57		NP_000258.1
NF1	NM_001128147.3	c.122A>T	p.Glu41Val	missense_variant	2/15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.122A>T	p.Glu41Val	missense_variant	2/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Sep 05, 2018	The variant has been observed in a patient with Neurofibromatosis type I. The variants is predicted to create a de novo donor splice site in exon 2 by in silico splicing tools. Functional RNA study has shown that the variant causes major splicing aberration - deletion of last 84 bp of exon 2, causing deletion of aminoacids 41-68 (PMID: 31507634, 34439939). Therefore the variant was classified as likely pathogenic (ACMG/AMP: PS3, PM2, PP3, and PP1 supporting). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 05, 2021	This sequence change replaces glutamic acid with valine at codon 41 of the NF1 protein (p.Glu41Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 28 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 31507634, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this variant is associated with the activation of a cryptic splice site in exon 2 (PMID: 31507634). This variant disrupts the p.Ser47 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27322474, 27716896, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Dr. med. U. Finckh, Human Genetics, Eurofins MVZ	Jun 20, 2021	The variant is not present in gnomAD (v.2.1.1). In silico tools predict the creation of a new splice donor in exon 2. It has been described in a proband with clinically diagnosed NF1 (PMID 31507634). RNA analysis reported in the same publication suggests the variant to lead to a skipping of 84bp (r.121_204del) with consecutive in-frame deletion of 28 amino acids (p.Glu41_Met68del). Internal data: heterozygous in a proband with clinically suspected NF1 but not in the unaffected parents (PM6). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	35
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.84	.;D;.;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	.;D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.029	.;D;D;T
Sift4G	Benign	0.086	.;T;T;T
Polyphen		0.99	D;P;D;.
Vest4		0.92, 0.92, 0.89
MutPred		0.36		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);
MVP		0.74
MPC		1.8
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs786203038; hg19: chr17-29483062;