17-31259077-C-T

Position:

• chr17-31259077-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4 BS2_Supporting

The NM_001042492.3(NF1):​c.4378C>T​(p.His1460Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,452,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.53

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 Likely_benign. Variant got -1 ACMG points.

• 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=0.39746326).
• BS2: High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NF1	NM_001042492.3	c.4378C>T	p.His1460Tyr	missense_variant	33/58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.4315C>T	p.His1439Tyr	missense_variant	32/57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.4378C>T	p.His1460Tyr	missense_variant	33/58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1452672 Hom.: 0 Cov.: 30 AF XY: 0.00000277 AC XY: 2 AN XY: 722084

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: 0.00000542

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00000825 AC: 1

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	Labcorp Genetics (formerly Invitae), Labcorp	Jun 04, 2022	This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1439 of the NF1 protein (p.His1439Tyr). 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: 232783). 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. This variant disrupts the p.His1439 amino acid residue in NF1. Other variant(s) that disrupt this residue have been observed in individuals with NF1-related conditions (PMID: 23668869, 27716896), which suggests that this may be a clinically significant amino acid residue. 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	Genome-Nilou Lab	Mar 15, 2022	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 17, 2021

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2015

The p.H1460Y variant (also known as c.4378C>T), located in coding exon 33 of the NF1 gene, results from a C to T substitution at nucleotide position 4378. The histidine at codon 1460 is replaced by tyrosine, an amino acid with similar properties. This variant was previously reported in the SNPDatabase as rs377295676. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.01% (1/13004) total alleles studied and 0.01% (1/8600) European American alleles. <span style="font-family:arial,sans-serif; font-size:9pt">This variant was not reported in the 1000 Genomes Project population-based cohort.To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55,000 alleles tested) in our clinical cohort.This amino acid position is well conserved in available vertebrate species, however tyrosine is the reference amino acid in three species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence is limited at this time, the clinical significance of p.H1460Y remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.87	D;.;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.025
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.40	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.8	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.11	T;T;T
Sift4G	Uncertain	0.0070	D;D;D
Polyphen		0.0	B;B;.
Vest4		0.41
MVP		0.68
MPC		0.80
ClinPred		0.88	D
GERP RS		3.5
Varity_R		0.75
gMVP		0.85

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: rs377295676; hg19: chr17-29586095;