17-31169997-G-C

Variant names:

• chr17-31169997-G-C
• rs876659079
• NM_001042492.3:c.586G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_001042492.3(NF1):​c.586G>C​(p.Glu196Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E196K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72
• Publications: 0 publications found

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]

NF1 Gene-Disease associations (from GenCC):

• neurofibromatosis type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
• Moyamoya disease

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 29 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-31169997-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 231304.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001042492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.586G>C	p.Glu196Gln	missense splice_region	Exon 5 of 58	NP_001035957.1
	NF1	NM_000267.4		c.586G>C	p.Glu196Gln	missense splice_region	Exon 5 of 57	NP_000258.1
	NF1	NM_001128147.3		c.586G>C	p.Glu196Gln	missense splice_region	Exon 5 of 15	NP_001121619.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.586G>C	p.Glu196Gln	missense splice_region	Exon 5 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.586G>C	p.Glu196Gln	missense splice_region	Exon 5 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.586G>C	p.Glu196Gln	missense splice_region	Exon 5 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 28, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.35		Gain of MoRF binding (P = 0.0348)
MVP		0.88
MPC		1.7
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.62
Mutation Taster		=15/85	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876659079; hg19: chr17-29497015;