rs758893131

chr17-31226621-A-Cchr17-31226621-A-Gchr17-31226621-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042492.3(NF1):c.2188A>C(p.Asn730His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. N730Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.88

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 1 ACMG points.

• 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=0.21199772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2188A>C	p.Asn730His	missense_variant	18/58	ENST00000358273.9
NF1	NM_000267.3	c.2188A>C	p.Asn730His	missense_variant	18/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2188A>C	p.Asn730His	missense_variant	18/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461576 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2021	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 229999). This variant has not been reported in the literature in individuals affected with NF1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 730 of the NF1 protein (p.Asn730His). -

Juvenile myelomonocytic leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 20, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2015

The p.N730H variant (also known as c.2188A>C), located in coding exon 18 of the NF1 gene, results from an A to C substitution at nucleotide position 2188. The asparagine at codon 730 is replaced by histidine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 110000alleles tested) in our clinical cohort.This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.N730Hremains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	22
Dann	Benign	0.81
DEOGEN2	Uncertain	0.49	T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.081
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	0.82	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.066
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.15
MutPred		0.44		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);.;
MVP		0.43
MPC		0.71
ClinPred		0.61	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.42

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: rs758893131; hg19: chr17-29553639;