17-31356988-G-C

Position:

• chr17-31356988-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001042492.3(NF1):​c.7767G>C​(p.Gln2589His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 0.829

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 Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10899013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.7767G>C	p.Gln2589His	missense_variant	53/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.7704G>C	p.Gln2568His	missense_variant	52/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.7767G>C	p.Gln2589His	missense_variant	53/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461648 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727112

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:3

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	Nov 04, 2023	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 2568 of the NF1 protein (p.Gln2568His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141997). 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 not expected to disrupt NF1 protein function with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Neurofibromatosis-Noonan syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Juvenile myelomonocytic leukemia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 13, 2023

- -

Neurofibromatosis, familial spinal Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Café-au-lait macules with pulmonary stenosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2020

The c.7704G>C (p.Q2568H) alteration is located in exon 52 (coding exon 52) of the NF1 gene. This alteration results from a G to C substitution at nucleotide position 7704, causing the glutamine (Q) at amino acid position 2568 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 21, 2014

The p.Q2589H variant (also known as c.7767G>C), located in coding exon 53 of the NF1 gene, results from a G to C substitution at nucleotide position 7767. The glutamine at codon 2589 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.To date, this alteration has been detected with an allele frequency of approximately 0.02% (greater than 5000 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign but deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.082
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.053	T;T;T
Polyphen		0.16	B;P;.
Vest4		0.33
MutPred		0.12		Loss of solvent accessibility (P = 0.0238);.;.;
MVP		0.46
MPC		0.49
ClinPred		0.67	D
GERP RS		2.7
Varity_R		0.12
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs587782168; hg19: chr17-29684006;