rs1555613598

Positions:

• chr17-31225215-G-A
• chr17-31225215-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4_Strong BP6

The NM_001042492.3(NF1):​c.1966G>A​(p.Ala656Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.426

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ: 6.5427 (greater than the threshold 3.09). Trascript score misZ: 8.4054 (greater than threshold 3.09). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. GenCC has associacion of the gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.
• BP4: Computational evidence support a benign effect (MetaRNN=0.064011246).
• BP6: Variant 17-31225215-G-A is Benign according to our data. Variant chr17-31225215-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 457557.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1966G>A	p.Ala656Thr	missense_variant	17/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1966G>A	p.Ala656Thr	missense_variant	17/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1966G>A	p.Ala656Thr	missense_variant	17/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2024

The p.A656T variant (also known as c.1966G>A), located in coding exon 17 of the NF1 gene, results from a G to A substitution at nucleotide position 1966. The alanine at codon 656 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved and threonine is a reference amino acid in several 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 this alteration remains unclear. -

Neurofibromatosis, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.43	T;.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.60	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.064	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;L;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.75	N;N;N
REVEL	Benign	0.055
Sift	Benign	0.074	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.13
MutPred		0.14		Gain of glycosylation at A656 (P = 0.0395);Gain of glycosylation at A656 (P = 0.0395);.;
MVP		0.20
MPC		0.67
ClinPred		0.12	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555613598; hg19: chr17-29552233;