17-31357290-A-G
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BS2
The NM_001042492.3(NF1):c.7891A>G(p.Thr2631Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000304 in 1,613,908 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001042492.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251294Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135808
GnomAD4 exome AF: 0.0000328 AC: 48AN: 1461680Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 24AN XY: 727136
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152228Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
Neurofibromatosis, type 1 Uncertain:3Benign:1
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This sequence change in NF1 is predicted to replace threonine with alanine at codon 2631, p.(Thr2631Ala). The threonine residue is highly conserved (92/95 vertebrates, UCSC), and is not located in an annotated domain. There is a small physicochemical difference between threonine and alanine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.002% (2/113,630 alleles) in the European (non-Finnish) population. This variant has been reported in at least one proband with sporadic neurofibromatosis type 1 and an individual with pheochromocytoma explained by a pathogenic variant in RET (PMID: 8544190, 24694336). The prevalence of the variant in individuals with breast cancer is not significantly increased compared with the prevalence in controls (PMID: 33471991). Computational evidence predicts a benign effect for the missense substitution (REVEL = 0.279). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: BP4. -
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not provided Uncertain:3Other:1
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In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in a patient with cutaneous features of neurofibromatosis type 1 (Upadhyaya et al., 1995); This variant is associated with the following publications: (PMID: 24694336, 34426522, 25486365, 8544190) -
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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
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Juvenile myelomonocytic leukemia Uncertain:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Uncertain:1
The c.7828A>G (p.T2610A) alteration is located in exon 53 (coding exon 53) of the NF1 gene. This alteration results from a A to G substitution at nucleotide position 7828, causing the threonine (T) at amino acid position 2610 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.T2631A variant (also known as c.7891A>G or p.T2610A or c.7828A>G), located in coding exon 54 of the NF1 gene, results from an A to G substitution at nucleotide position 7891. The threonine at codon 2631 is replaced by alanine, an amino acid with similar properties. This alteration has beendetected in an individual with a clinical diagnosis of neurofibromatosis type 1 (NF1) (Upadhyaya M,J. Med. Genet. 1995 Sep; 32(9):706-10).This variant was previously reported in the SNPDatabase as rs199474793. This variant was not reported in population-based cohorts in the following databases:NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.003% (greater than 30000alleles tested) in our clinical cohort.This amino acid position is 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 p.T2631Aremains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at