17-31156044-A-T

Variant names:

• chr17-31156044-A-T
• rs786203038
• NM_001042492.3:c.122A>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):​c.122A>T​(p.Glu41Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E41A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.78
• Publications: 3 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 14 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 28 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-31156044-A-T is Pathogenic according to our data. Variant chr17-31156044-A-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 586954.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.122A>T	p.Glu41Val	missense	Exon 2 of 58	NP_001035957.1
	NF1	NM_000267.4		c.122A>T	p.Glu41Val	missense	Exon 2 of 57	NP_000258.1
	NF1	NM_001128147.3		c.122A>T	p.Glu41Val	missense	Exon 2 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.122A>T	p.Glu41Val	missense	Exon 2 of 58	ENSP00000351015.4
	NF1	ENST00000356175.7	TSL:1	c.122A>T	p.Glu41Val	missense	Exon 2 of 57	ENSP00000348498.3
	NF1	ENST00000431387.8	TSL:1	c.122A>T	p.Glu41Val	missense	Exon 2 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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Jun 20, 2021

Dr. med. U. Finckh, Human Genetics, Eurofins MVZ

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not present in gnomAD (v.2.1.1). In silico tools predict the creation of a new splice donor in exon 2. It has been described in a proband with clinically diagnosed NF1 (PMID 31507634). RNA analysis reported in the same publication suggests the variant to lead to a skipping of 84bp (r.121_204del) with consecutive in-frame deletion of 28 amino acids (p.Glu41_Met68del). Internal data: heterozygous in a proband with clinically suspected NF1 but not in the unaffected parents (PM6).

Sep 05, 2018

Department of Molecular Diagnostics, Institute of Oncology Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been observed in a patient with Neurofibromatosis type I. The variants is predicted to create a de novo donor splice site in exon 2 by in silico splicing tools. Functional RNA study has shown that the variant causes major splicing aberration - deletion of last 84 bp of exon 2, causing deletion of aminoacids 41-68 (PMID: 31507634, 34439939). Therefore the variant was classified as likely pathogenic (ACMG/AMP: PS3, PM2, PP3, and PP1 supporting).

Apr 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 31507634, Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Studies have shown that this variant is associated with the activation of a cryptic splice site in exon 2 (PMID: 31507634). This variant disrupts the p.Ser47 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27322474, 27716896, Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces glutamic acid with valine at codon 41 of the NF1 protein (p.Glu41Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 28 amino acid residue(s), but is expected to preserve the integrity of the reading-frame.

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

Feb 28, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.122A>T variant (also known as p.E41V), located in coding exon 2 of the NF1 gene, results from an A to T substitution at nucleotide position 122. The glutamic acid at codon 41 is replaced by valine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with Neurofibromatosis type 1 (Setrajcic Dragos V et al. Front Genet, 2019 Aug;10:762). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Setrajcic Dragos V et al. Front Genet, 2019 Aug;10:762; Dragoš VŠ et al. Biology (Basel), 2021 Jul;10). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	35
DANN	Benign	0.94
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.8
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.029	D
Sift4G	Benign	0.086	T
Polyphen		0.99	D
Vest4		0.92
MutPred		0.36		Gain of sheet (P = 0.0043)
MVP		0.74
MPC		1.8
ClinPred		0.97	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.69
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: -2

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

Other links and lift over

dbSNP: rs786203038; hg19: chr17-29483062;