rs750869272

Positions:

• chr17-31338101-C-G
• chr17-31338101-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP2 BP4

The NM_001042492.3(NF1):​c.6781C>G​(p.His2261Asp) 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 benign outcome for this variant. 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. H2261Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.39

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a helix (size 19) in uniprot entity NF1_HUMAN there are 11 pathogenic changes around while only 3 benign (79%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NF1
• BP4: Computational evidence support a benign effect (MetaRNN=0.38496333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.6781C>G	p.His2261Asp	missense_variant	45/58	ENST00000358273.9
NF1	NM_000267.3	c.6718C>G	p.His2240Asp	missense_variant	44/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.6781C>G	p.His2261Asp	missense_variant	45/58	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

Jan 02, 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 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"). 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 histidine with aspartic acid at codon 2240 of the NF1 protein (p.His2240Asp). The histidine residue is highly conserved and there is a moderate physicochemical difference between histidine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Benign	0.38	T;.;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.084
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.38	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.14	N;N;N
REVEL	Uncertain	0.35
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.61	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.80
MutPred		0.40		Loss of MoRF binding (P = 0.0673);.;.;
MVP		0.85
MPC		2.6
ClinPred		0.86	D
GERP RS		4.5
Varity_R		0.28
gMVP		0.67

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: rs750869272; hg19: chr17-29665119;