17-31219072-T-G

Variant names:

• chr17-31219072-T-G
• rs199474737
• NM_001042492.3:c.1595T>G

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.1595T>G​(p.Leu532Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L532P) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.44
• Publications: 12 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 21 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 chr17-31219072-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 68302.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 17-31219072-T-G is Pathogenic according to our data. Variant chr17-31219072-T-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 237521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1595T>G	p.Leu532Arg	missense	Exon 14 of 58	NP_001035957.1
	NF1	NM_000267.4		c.1595T>G	p.Leu532Arg	missense	Exon 14 of 57	NP_000258.1
	NF1	NM_001128147.3		c.1595T>G	p.Leu532Arg	missense	Exon 14 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.1595T>G	p.Leu532Arg	missense	Exon 14 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.1595T>G	p.Leu532Arg	missense	Exon 14 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.1595T>G	p.Leu532Arg	missense	Exon 14 of 15	ENSP00000412921.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:1

May 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant disrupts the p.Leu532 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. 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. This sequence change replaces leucine with arginine at codon 532 of the NF1 protein (p.Leu532Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of neurofibromatosis (PMID: 30014477, 31370276, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 237521).

Juvenile myelomonocytic leukemia Pathogenic:1

Jul 19, 2022

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Pathogenic:1

May 03, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L532R variant (also known as c.1595T>G), located in coding exon 14 of the NF1 gene, results from a T to G substitution at nucleotide position 1595. The leucine at codon 532 is replaced by arginine, an amino acid with dissimilar properties. This variant was detected in an individual meeting diagnostic criteria for neurofibromatosis type I (NF1) in our laboratory (Ambry internal data). A different amino acid substitution at the same codon (p.L532P) was also identified in an patient affected with NF1 (Mattocks C et al. J. Med. Genet., 2004 Apr;41:e48). This amino acid position is highly conserved in available vertebrate species. 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.86	D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.4
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.59		Gain of disorder (P = 0.0446)
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.94
Mutation Taster		=0/100	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: rs199474737; hg19: chr17-29546090;