rs1060500367

Positions:

• chr17-31229149-G-A
• chr17-31229149-G-C
• chr17-31229149-G-T

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.2534G>A​(p.Cys845Tyr) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C845R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.59

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 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 chr17-31229148-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 404431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882
• PP5: Variant 17-31229149-G-A is Pathogenic according to our data. Variant chr17-31229149-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 404587.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31229149-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.2534G>A	p.Cys845Tyr	missense_variant	21/58	ENST00000358273.9
NF1	NM_000267.3	c.2534G>A	p.Cys845Tyr	missense_variant	21/57

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.2534G>A	p.Cys845Tyr	missense_variant	21/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 22, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys845 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. 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: 404587). This missense change has been observed in individual(s) with neurofibromatosis type 1 (NF1) and features of NF1 (PMID: 23656349, 29290338; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 845 of the NF1 protein (p.Cys845Tyr). -
Pathogenic, criteria provided, single submitter	clinical testing	Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center	Feb 26, 2021	The c.2534G>A variant in the NF1 gene is a heterozygous missense variant, which results in the substitution of the conserved cysteine residue at the 845 position to tyrosine (p.Cys845Tyr). This variant has been observed in the heterozygous state in multiple individuals with clinical features of Neurofibromatosis, type 1 (PMIDs: 29290338, 23656349, and 30014477) and has been reported in ClinVar as Pathogenic (Variation ID: 404587; Last accessed: 2/25/2021). It falls in the cysteine-serine-rich domain of the protein, and variants in codons 844-848 have been shown to be associated with a more severe presentation of neurofibromatosis type 1. Additionally, variants in these codons were identified in ~0.8% of unrelated variant-positive individuals in a large cohort of individuals with NF1, suggesting a mutational hotspot (PMID: 29290338). This variant is not observed in the Genome Aggregation Database (gnomAD), indicating it is not a common benign variant in the populations represented in this database. In addition, a different missense variant in the same position, c.2533T>C, p.Cys845Arg has also been reported in the ClinVar database as Pathogenic (Variation ID: 404431; Last accessed: 2/25/2021). -
Pathogenic, criteria provided, single submitter	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	Jun 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;.;D
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.4	D;D;D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.88	P;P;.
Vest4		0.92
MutPred		0.71		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;
MVP		0.74
MPC		1.4
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.85
gMVP		0.88

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: rs1060500367; hg19: chr17-29556167; COSMIC: COSV62193778; COSMIC: COSV62193778;