17-31227539-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_001042492.3(NF1):c.2342A>G(p.His781Arg) 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. H781P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.80

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 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 chr17-31227539-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68317.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, not_provided=1, Uncertain_significance=1}.
• PP2: Missense variant where missense usually causes diseases, NF1

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2342A>G	p.His781Arg	missense_variant	20/58	ENST00000358273.9
NF1	NM_000267.3	c.2342A>G	p.His781Arg	missense_variant	20/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2342A>G	p.His781Arg	missense_variant	20/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with NF1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with arginine at codon 781 of the NF1 protein (p.His781Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.78	D;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.69	N;N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.0	D;D;D
REVEL	Benign	0.25
Sift	Benign	0.075	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.75
MutPred		0.42		Gain of MoRF binding (P = 0.0149);Gain of MoRF binding (P = 0.0149);.;
MVP		0.80
MPC		0.87
ClinPred		0.84	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs199474763; hg19: chr17-29554557;