17-31201044-T-G

Variant names:

• chr17-31201044-T-G
• rs137854563
• NM_001042492.3:c.1070T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_001042492.3(NF1):​c.1070T>G​(p.Leu357Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L357V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.85
• Publications: 6 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 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 28 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 chr17-31201044-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 17-31201044-T-G is Pathogenic according to our data. Variant chr17-31201044-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 232517.

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.1070T>G	p.Leu357Arg	missense	Exon 10 of 58	NP_001035957.1
	NF1	NM_000267.4		c.1070T>G	p.Leu357Arg	missense	Exon 10 of 57	NP_000258.1
	NF1	NM_001128147.3		c.1070T>G	p.Leu357Arg	missense	Exon 10 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.1070T>G	p.Leu357Arg	missense	Exon 10 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.1070T>G	p.Leu357Arg	missense	Exon 10 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.1070T>G	p.Leu357Arg	missense	Exon 10 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Jan 10, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 02, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L357R variant (also known as c.1070T>G), located in coding exon 10 of the NF1 gene, results from a T to G substitution at nucleotide position 1070. The leucine at codon 357 is replaced by arginine, an amino acid with dissimilar properties. One study identified this alteration in one patient out of 521 patients with neurofibromatosis (FahsoldR, Am. J. Hum. Genet. 2000 Mar; 66(3):790-818). In addition, this alteration showed perfect segregation with eight individuals in one family with neurofibromatosis. The alteration was present in six affected individuals across three generations, and was not detected in two healthy individuals (MessiaenL, J. Med. Genet. 2003 Feb; 40(2):122-6). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000 alleles tested) in our clinical cohort.In addition, this alteration is predicted to be deleterious by in silico analysis.Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Neurofibromatosis, type 1 Uncertain:1

Mar 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function. ClinVar contains an entry for this variant (Variation ID: 232517). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 357 of the NF1 protein (p.Leu357Arg).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.64	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.72		Loss of helix (P = 0.0104)
MVP		0.89
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.96
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137854563; hg19: chr17-29528062;