rs1555613556

chr17-31225118-C-Gchr17-31225118-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001042492.3(NF1):c.1869C>G(p.His623Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. H623R) 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, single submitter U:1
• Conservation: PhyloP100: -0.0640

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 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain 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=0.17988387).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1869C>G	p.His623Gln	missense_variant	17/58	ENST00000358273.9
NF1	NM_000267.3	c.1869C>G	p.His623Gln	missense_variant	17/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1869C>G	p.His623Gln	missense_variant	17/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461474 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727040

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 11, 2023

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 623 of the NF1 protein (p.His623Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1392515). 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 with a negative predictive value of 95%. 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	Benign	0.15
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Benign	0.96
DEOGEN2	Uncertain	0.55	D;.;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.34	N;N;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.044	D;T;D
Sift4G	Benign	0.34	T;T;T
Polyphen		0.40	B;P;.
Vest4		0.85
MutPred		0.29		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);.;
MVP		0.76
MPC		0.70
ClinPred		0.37	T
GERP RS		0.48
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.063
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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: chr17-29552136;