rs1324833228

Variant names:

• chr17-31206335-A-C
• rs1324833228
• NM_001042492.3:c.1356A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-31206335-A-C
• chr17-31206335-A-G
• chr17-31206335-A-T

Variant summary

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

The NM_001042492.3(NF1):​c.1356A>C​(p.Gln452His) 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. Q452L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.854
• Publications: 2 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 0 benign, 42 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.1356A>C	p.Gln452His	missense_variant	Exon 12 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.4	c.1356A>C	p.Gln452His	missense_variant	Exon 12 of 57		NP_000258.1
NF1	NM_001128147.3	c.1356A>C	p.Gln452His	missense_variant	Exon 12 of 15		NP_001121619.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.1356A>C	p.Gln452His	missense_variant	Exon 12 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 480174). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This sequence change replaces glutamine with histidine at codon 452 of the NF1 protein (p.Gln452His). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and histidine. -

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

Nov 10, 2016

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q452H variant (also known as c.1356A>C), located in coding exon 12 of the NF1 gene, results from an A to C substitution at nucleotide position 1356. The glutamine at codon 452 is replaced by histidine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 175000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Benign	0.22
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.78	.;D;.;.;T
Eigen	Benign	0.084
Eigen_PC	Benign	0.065
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Uncertain	0.63	D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.1	M;M;M;M;.
PhyloP100		0.85
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.3	.;D;D;D;D
REVEL	Uncertain	0.61
Sift	Benign	0.090	.;T;T;D;T
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		0.99	D;B;D;.;.
Vest4		0.83, 0.81, 0.74
MutPred		0.31		Loss of solvent accessibility (P = 0.0056);Loss of solvent accessibility (P = 0.0056);Loss of solvent accessibility (P = 0.0056);Loss of solvent accessibility (P = 0.0056);.;
MVP		0.93
MPC		1.7
ClinPred		0.93	D
GERP RS		0.21
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.47
Mutation Taster		=25/75	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: rs1324833228; hg19: chr17-29533353;