rs199474770

Variant names:

• chr17-31219033-A-C
• rs199474770
• NM_001042492.3:c.1556A>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001042492.3(NF1):​c.1556A>C​(p.Gln519Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 6.64

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.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1556A>C	p.Gln519Pro	missense_variant	Exon 14 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1556A>C	p.Gln519Pro	missense_variant	Exon 14 of 57		NP_000258.1
NF1	NM_001128147.3	c.1556A>C	p.Gln519Pro	missense_variant	Exon 14 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1556A>C	p.Gln519Pro	missense_variant	Exon 14 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

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UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	0.0017	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	.;D;.;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;M;M;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.6	.;D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.013	.;D;D;D;D
Sift4G	Uncertain	0.0040	.;D;D;D;D
Polyphen		0.94	P;D;B;.;.
Vest4		0.69, 0.69, 0.65
MutPred		0.40		Gain of glycosylation at Q519 (P = 0.0087);Gain of glycosylation at Q519 (P = 0.0087);Gain of glycosylation at Q519 (P = 0.0087);Gain of glycosylation at Q519 (P = 0.0087);.;
MVP		0.58
MPC		1.0
ClinPred		0.97	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.86

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: rs199474770; hg19: chr17-29546051; COSMIC: COSV62198784;