17-31260441-C-G

Variant names:

• chr17-31260441-C-G
• rs577394398
• NM_001042492.3:c.4503C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001042492.3(NF1):​c.4503C>G​(p.Asp1501Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1501Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.819
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 30 uncertain in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4503C>G	p.Asp1501Glu	missense_variant	Exon 34 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.4440C>G	p.Asp1480Glu	missense_variant	Exon 33 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4503C>G	p.Asp1501Glu	missense_variant	Exon 34 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1480E variant (also known as c.4440C>G), located in coding exon 33 of the NF1 gene, results from a C to G substitution at nucleotide position 4440. The aspartic acid at codon 1480 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		0.82
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.5	D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.22	T;T;T
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.98	D;D;.
Vest4		0.80
MutPred		0.42		Gain of solvent accessibility (P = 0.1376);.;.;
MVP		0.88
MPC		1.7
ClinPred		0.98	D
GERP RS		3.8
Varity_R		0.52
gMVP		0.61
Mutation Taster		=20/80	disease causing

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: rs577394398; hg19: chr17-29587459;