17-31214530-A-G
Variant summary
Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM1BP4_ModerateBS2_Supporting
The NM_001042492.3(NF1):c.1472A>G(p.Tyr491Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,460,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y491N) has been classified as Uncertain significance.
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
Publications
- neurofibromatosis type 1Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, PanelApp Australia, G2P, Genomics England PanelApp
- neurofibromatosis-Noonan syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, PanelApp Australia
- Moyamoya diseaseInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary pheochromocytoma-paragangliomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NF1 | NM_001042492.3 | c.1472A>G | p.Tyr491Cys | missense_variant | Exon 13 of 58 | ENST00000358273.9 | NP_001035957.1 | |
NF1 | NM_000267.4 | c.1472A>G | p.Tyr491Cys | missense_variant | Exon 13 of 57 | NP_000258.1 | ||
NF1 | NM_001128147.3 | c.1472A>G | p.Tyr491Cys | missense_variant | Exon 13 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD2 exomes AF: 0.00000798 AC: 2AN: 250650 AF XY: 0.00000738 show subpopulations
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1460074Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15AN XY: 726466 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Uncertain:2Other:1
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In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 10712197) -
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Neurofibromatosis, type 1 Uncertain:1Benign:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The p.Y491C variant (also known as c.1472A>G), located in coding exon 13 of the NF1 gene, results from an A to G substitution at nucleotide position 1472. The tyrosine at codon 491 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was identified in two individuals with neurofibromatosis type 1 in a study of more than 500 neurofibromatosis type 1 probands (Fahsold R et al. Am. J. Hum. Genet., 2000 Mar;66:790-818). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at