chr17-31095326-C-T

Position:

• chr17-31095326-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001042492.3(NF1):​c.17C>T​(p.Pro6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,648 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.87

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]

MIR4733HG (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• 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.17C>T	p.Pro6Leu	missense_variant	1/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.17C>T	p.Pro6Leu	missense_variant	1/57		NP_000258.1
NF1	NM_001128147.3	c.17C>T	p.Pro6Leu	missense_variant	1/15		NP_001121619.1
MIR4733HG	NR_186435.1	n.165G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.17C>T	p.Pro6Leu	missense_variant	1/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1386648 Hom.: 0 Cov.: 33 AF XY: 0.00000292 AC XY: 2 AN XY: 684136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 14, 2023	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. 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: 219691). This variant has not been reported in the literature in individuals affected with NF1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 6 of the NF1 protein (p.Pro6Leu). -

Neurofibromatosis, type 1;C0349639:Juvenile myelomonocytic leukemia;C0553586:Café-au-lait macules with pulmonary stenosis;C1834235:Neurofibromatosis, familial spinal;C2931482:Neurofibromatosis-Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 24, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The p.P6L variant (also known as c.17C>T), located in coding exon 1 of the NF1 gene, results from a C to T substitution at nucleotide position 17. The proline at codon 6 is replaced by leucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	.;D;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Pathogenic	0.96	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.5	M;M;M;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.7	.;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.0040	.;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.19, 0.19, 0.43
MutPred		0.38		Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);Gain of helix (P = 0.0022);
MVP		0.59
MPC		0.72
ClinPred		1.0	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.49
gMVP		0.97

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: rs864622210; hg19: chr17-29422344;