NM_001042492.3:c.2542G>C

Variant names:

• chr17-31229157-G-C
• rs1060500368
• NM_001042492.3:c.2542G>C

Variant summary

Our verdict is Pathogenic. The variant received 30 ACMG points: 30P and 0B. PS1_Very_Strong PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.2542G>C​(p.Gly848Arg) 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000542198: Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NF1 function (PMID:26908603, 27482814)." and additional evidence is available in ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G848E) has been classified as 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:6
• Conservation: PhyloP100: 9.56
• Publications: 22 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• neurofibromatosis-Noonan syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 30 ACMG points.

• PS1: Transcript NM_001042492.3 (NF1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000542198: Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on NF1 function (PMID: 26908603, 27482814).; SCV001176749: While mouse models harboring this mutation did not recapitulate the phenotype in humans, these mice had reduced neurofibromin expression (Li K et al. Dis Model Mech, 2016 07;9:759-67; Toonen JA et al. Hum. Mol. Genet., 2016 05;25:1703-13).
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 33 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 chr17-31229158-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 68324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 17-31229157-G-C is Pathogenic according to our data. Variant chr17-31229157-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 404588.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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	NM_001042492.3	MANE Select	c.2542G>C	p.Gly848Arg	missense	Exon 21 of 58	NP_001035957.1	P21359-1
	NF1	NM_000267.4		c.2542G>C	p.Gly848Arg	missense	Exon 21 of 57	NP_000258.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NF1	ENST00000358273.9	TSL:1 MANE Select	c.2542G>C	p.Gly848Arg	missense	Exon 21 of 58	ENSP00000351015.4	P21359-1
	NF1	ENST00000356175.7	TSL:1	c.2542G>C	p.Gly848Arg	missense	Exon 21 of 57	ENSP00000348498.3	P21359-2
	NF1	ENST00000579081.6	TSL:1	n.2542G>C		non_coding_transcript_exon	Exon 21 of 58	ENSP00000462408.2	J3KSB5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Neurofibromatosis, type 1 (4)
1	-	-	Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.8	L
PhyloP100		9.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.92		Gain of MoRF binding (P = 0.0316)
MVP		0.90
MPC		1.9
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.93
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1060500368; hg19: chr17-29556175;