rs1555611582

Variant names:

• chr17-31206310-G-A
• rs1555611582
• NM_001042492.3:c.1331G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-31206310-G-A
• chr17-31206310-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.1331G>A​(p.Gly444Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,610 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: 0.0000014 (0 hom.)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.61

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NF1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 399 curated pathogenic missense variants (we use a threshold of 10). The gene has 143 curated benign missense variants. Gene score misZ: 6.5427 (above the threshold of 3.09). Trascript score misZ: 8.4054 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.23862141).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.1331G>A	p.Gly444Asp	missense_variant	Exon 12 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.1331G>A	p.Gly444Asp	missense_variant	Exon 12 of 57		NP_000258.1
NF1	NM_001128147.3	c.1331G>A	p.Gly444Asp	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.1331G>A	p.Gly444Asp	missense_variant	Exon 12 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461610 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727114

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: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurofibromatosis, type 1 Uncertain:2

Jul 30, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with NF1-related disease. ClinVar contains an entry for this variant (Variation ID: 527456). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 444 of the NF1 protein (p.Gly444Asp). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Apr 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Apr 17, 2018

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is denoted NF1 c.1331G>A at the cDNA level, p.Gly444Asp (G444D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. NF1 Gly444Asp was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether NF1 Gly444Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

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

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G444D variant (also known as c.1331G>A), located in coding exon 12 of the NF1 gene, results from a G to A substitution at nucleotide position 1331. The glycine at codon 444 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.089	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;T;.;.;T
Eigen	Benign	-0.012
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.0	N;N;N;N;.
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.83	.;N;N;N;N
REVEL	Benign	0.28
Sift	Benign	0.63	.;T;T;T;T
Sift4G	Benign	0.35	.;T;T;T;T
Polyphen		0.45	B;B;B;.;.
Vest4		0.64, 0.70, 0.70
MutPred		0.57		Gain of ubiquitination at K449 (P = 0.1115);Gain of ubiquitination at K449 (P = 0.1115);Gain of ubiquitination at K449 (P = 0.1115);Gain of ubiquitination at K449 (P = 0.1115);.;
MVP		0.75
MPC		0.90
ClinPred		0.51	D
GERP RS		6.2
Varity_R		0.14
gMVP		0.57

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: rs1555611582; hg19: chr17-29533328;