chr17-31258500-A-C

Position:

• chr17-31258500-A-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001042492.3(NF1):​c.4330A>C​(p.Lys1444Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. K1444E) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense, splice_region
• Scores: Splicing: ADA: 0.9121
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.91

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a helix (size 18) in uniprot entity NF1_HUMAN there are 15 pathogenic changes around while only 0 benign (100%) 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 chr17-31258500-A-G is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 17-31258500-A-C is Pathogenic according to our data. Variant chr17-31258500-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 431637.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-31258500-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4330A>C	p.Lys1444Gln	missense_variant, splice_region_variant	32/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4267A>C	p.Lys1423Gln	missense_variant, splice_region_variant	31/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4330A>C	p.Lys1444Gln	missense_variant, splice_region_variant	32/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 01, 2023	This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1423 of the NF1 protein (p.Lys1423Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with NF1-related conditions (PMID: 31595648). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 431637). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NF1 function (PMID: 8264648). This variant disrupts the p.Lys1423 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1568247, 11857752, 16380919, 16786508, 22807134, 23244495, 27322474). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	UAB Medical Genomics Laboratory, UAB Medicine	Jun 05, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Medical Genetics, University of Parma	Aug 17, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 26, 2023

Published functional studies demonstrate a damaging effect: decreased GAP activity and affinity for Ras and reduced ability of neurofibromin to associate with microtubules (Xu and Gutmann, 1997; Poullet et al., 1994); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31066482, 23656349, 27716896, 29290338, 9219873, 25486365, 22807134, 8264648, 34080803, 31595648) -

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2021

The p.K1423Q pathogenic mutation (also known as c.4267A>C), located in coding exon 31 of the NF1 gene, results from an A to C substitution at nucleotide position 4267. The lysine at codon 1423 is replaced by glutamine, an amino acid with similar properties. This alteration has been identified in multiple individuals with a clinical diagnosis of neurofibromatosis type 1 (Koczkowska M et al. Hum Mutat, 2020 01;41:299-315). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T;T;T
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.5	M;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.012	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.90		Loss of MoRF binding (P = 0.0324);.;.;
MVP		0.99
MPC		1.8
ClinPred		0.99	D
GERP RS		6.0
Varity_R		0.93
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Pathogenic	0.81
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: rs137854550; hg19: chr17-29585518; COSMIC: COSV62222725; COSMIC: COSV62222725;