17-31181462-G-C

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.627G>C(p.Gln209His) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q209Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

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 helix (size 20) in uniprot entity NF1_HUMAN there are 7 pathogenic changes around while only 1 benign (88%) 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=0.23515314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.627G>C	p.Gln209His	missense_variant	6/58	ENST00000358273.9
NF1	NM_000267.3	c.627G>C	p.Gln209His	missense_variant	6/57
NF1	NM_001128147.3	c.627G>C	p.Gln209His	missense_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.627G>C	p.Gln209His	missense_variant	6/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	17
Dann	Benign	0.79
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.1	L;L;L;L;.
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Pathogenic	0.82	D
Polyphen		0.0020	B;B;P;.;.
Vest4		0.90, 0.91, 0.96
MutPred		0.38		Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);Loss of MoRF binding (P = 0.0919);.;
MVP		0.98
MPC		1.7
ClinPred		0.31	T
GERP RS		0.0077
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29508480;