rs1060503913

Variant names:

• chr17-31156049-C-A
• NM_001042492.3:c.127C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31156049-C-A
• chr17-31156049-C-G
• chr17-31156049-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM2 PM5 PP2 BP4

The NM_001042492.3(NF1):​c.127C>A​(p.Leu43Ile) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L43P) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31156050-T-C is described in Lovd as [Pathogenic].
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.37028658).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.127C>A	p.Leu43Ile	missense_variant	Exon 2 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.127C>A	p.Leu43Ile	missense_variant	Exon 2 of 57		NP_000258.1
NF1	NM_001128147.3	c.127C>A	p.Leu43Ile	missense_variant	Exon 2 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.127C>A	p.Leu43Ile	missense_variant	Exon 2 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Uncertain	0.58	.;D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.37	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.3	.;N;N;N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	.;D;D;D
Sift4G	Uncertain	0.018	.;D;D;T
Polyphen		0.97	D;P;D;.
Vest4		0.68, 0.71
MutPred		0.33		Loss of catalytic residue at L43 (P = 0.0011);Loss of catalytic residue at L43 (P = 0.0011);Loss of catalytic residue at L43 (P = 0.0011);Loss of catalytic residue at L43 (P = 0.0011);
MVP		0.46
MPC		1.7
ClinPred		0.90	D
GERP RS		4.0
Varity_R		0.49
gMVP		0.46

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: chr17-29483067;