17-31325926-A-C

Position:

• chr17-31325926-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001042492.3(NF1):​c.4942A>C​(p.Thr1648Pro) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1648A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a region_of_interest Lipid binding (size 257) in uniprot entity NF1_HUMAN there are 37 pathogenic changes around while only 10 benign (79%) in NM_001042492.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NF1. . Gene score misZ 6.5427 (greater than the threshold 3.09). Trascript score misZ 8.4054 (greater than threshold 3.09). GenCC has associacion of gene with neurofibromatosis, familial spinal, hereditary pheochromocytoma-paraganglioma, neurofibromatosis type 1, Watson syndrome, neurofibromatosis-Noonan syndrome, Moyamoya disease, familial ovarian cancer.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4942A>C	p.Thr1648Pro	missense_variant	37/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4879A>C	p.Thr1627Pro	missense_variant	36/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4942A>C	p.Thr1648Pro	missense_variant	37/58	1	NM_001042492.3	ENSP00000351015	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1627 of the NF1 protein (p.Thr1627Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of NF1-related conditions (PMID: 23913538). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.91	D;.;T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.088	T;T;T
Sift4G	Benign	0.090	T;T;T
Polyphen		0.23	B;B;.
Vest4		0.47
MutPred		0.47		Gain of relative solvent accessibility (P = 0.0479);.;.;
MVP		0.68
MPC		1.0
ClinPred		0.97	D
GERP RS		4.7
Varity_R		0.92
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-29652944;