rs1555533328

chr17-31325968-T-Achr17-31325968-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001042492.3(NF1):c.4984T>A(p.Trp1662Arg) 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 Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1662L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain CRAL-TRIO (size 158) in uniprot entity NF1_HUMAN there are 65 pathogenic changes around while only 11 benign (86%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.936

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.4984T>A	p.Trp1662Arg	missense_variant	37/58	ENST00000358273.9
NF1	NM_000267.3	c.4921T>A	p.Trp1641Arg	missense_variant	36/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.4984T>A	p.Trp1662Arg	missense_variant	37/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Jun 22, 2020

This variant has not been reported in the literature in individuals with NF1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with arginine at codon 1641 of the NF1 protein (p.Trp1641Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. 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"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Pathogenic	34
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	-0.024	T
MutationAssessor	Uncertain	2.6	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-11	D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.92
MutPred		0.71		Gain of methylation at W1662 (P = 0.014);.;.;
MVP		0.81
MPC		2.3
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.38		Position offset: 1

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: chr17-29652986;