17-31230908-T-G

Variant names:

• chr17-31230908-T-G
• rs1555614646
• NM_001042492.3:c.3180T>G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001042492.3(NF1):​c.3180T>G​(p.Asp1060Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: NF1 NM_001042492.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.54

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 5 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NF1	NM_001042492.3	c.3180T>G	p.Asp1060Glu	missense_variant	Exon 24 of 58	ENST00000358273.9	NP_001035957.1
NF1	NM_000267.3	c.3180T>G	p.Asp1060Glu	missense_variant	Exon 24 of 57		NP_000258.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NF1	ENST00000358273.9	c.3180T>G	p.Asp1060Glu	missense_variant	Exon 24 of 58	1	NM_001042492.3	ENSP00000351015.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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 11, 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 sequence change replaces aspartic acid with glutamic acid at codon 1060 of the NF1 protein (p.Asp1060Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 527474). 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. 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. -

Mar 15, 2022

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Oct 14, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NF1 c.3180T>G; p.Asp1060Glu variant (rs1555614646) to our knowledge, is not reported in the medical literature but is reported in a gene-specific database (see link below) and in the ClinVar database (Variation ID: 527474). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 1060 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.179). Due to limited information, the clinical significance of the p.Asp1060Glu variant is uncertain at this time. References: Link to NF1 database: https://databases.lovd.nl/shared/genes/NF1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.6	D;D;N
REVEL	Benign	0.18
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		0.93	P;D;.
Vest4		0.74
MutPred		0.31		Gain of methylation at K1062 (P = 0.0788);Gain of methylation at K1062 (P = 0.0788);.;
MVP		0.83
MPC		1.6
ClinPred		0.96	D
GERP RS		0.65
Varity_R		0.37
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 0
DS_DL_spliceai		0.23		Position offset: 17

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555614646; hg19: chr17-29557926;