rs137854563

chr17-31201044-T-Cchr17-31201044-T-G

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM1 PM2 PM5 PP2 PP3_Moderate PP5_Very_Strong

The NM_001042492.3(NF1):c.1070T>C(p.Leu357Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. L357R) has been classified as Likely 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: 5.85

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 Pathogenic. Variant got 17 ACMG points.

• PM1: In a helix (size 16) in uniprot entity NF1_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) 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 chr17-31201044-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 232517.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.
• PP2: Missense variant where missense usually causes diseases, NF1
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 17-31201044-T-C is Pathogenic according to our data. Variant chr17-31201044-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NF1	NM_001042492.3	c.1070T>C	p.Leu357Pro	missense_variant	10/58	ENST00000358273.9
NF1	NM_000267.3	c.1070T>C	p.Leu357Pro	missense_variant	10/57
NF1	NM_001128147.3	c.1070T>C	p.Leu357Pro	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NF1	ENST00000358273.9	c.1070T>C	p.Leu357Pro	missense_variant	10/58	1	NM_001042492.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 06, 2023	This missense change has been observed in individual(s) with a diagnosis or clinical features of neurofibromatosis type 1 (PMID: 10712197, 12566521, 19221814, 30530636). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 357 of the NF1 protein (p.Leu357Pro). ClinVar contains an entry for this variant (Variation ID: 368). For these reasons, this variant has been classified as Pathogenic. 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2000	- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 04, 2022

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Jul 23, 2021

This variant has been reported in individuals and families affected with Neurofibromatosis type 1 including spinal tumors and breast cancer in the published literature (PMIDs: 10712197 (2000), 12566521 (2003), 19221814 (2009), and 30530636 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is disease causing and damaging. Based on the available information, the variant is predicted to be likely pathogenic. -

Neurofibromatosis, familial spinal Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2000

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
Cadd	Pathogenic	28
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.5	M;M;M;M;.
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.84	D
Polyphen		1.0	D;D;D;.;.
Vest4		0.98, 0.99, 0.99
MutPred		0.66		Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);Gain of loop (P = 0.0013);.;
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.94
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: rs137854563; hg19: chr17-29528062; COSMIC: COSV105917421;