NM_001042492.3:c.3604G>T
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP6BS2
The NM_001042492.3(NF1):c.3604G>T(p.Ala1202Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,020 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1202A) has been classified as Likely benign.
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 -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461874Hom.: 0 Cov.: 33 AF XY: 0.0000399 AC XY: 29AN XY: 727242 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74328 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not provided Uncertain:3
BS3_supporting, PM2 -
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In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: normal binding of NF1 to SPRED1 (Hirata 2016); Observed in individuals with suspected neurofibromatosis type 1 (Griffiths 2007, Hirata 2016); This variant is associated with the following publications: (PMID: 26635368, 16944272, 25486365, 22807134) -
Neurofibromatosis, type 1 Uncertain:1Benign:1
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NF1-related disorder Uncertain:1
The NF1 c.3604G>T variant is predicted to result in the amino acid substitution p.Ala1202Ser. This variant has been reported in a patient with either a clinical diagnosis or family history of neurofibromatosis (Griffiths et al. 2007. PubMed ID: 16944272). This variant was also reported in a patient with café-au lait macules and their father with a single café- au lait macule, and was classified as benign (Table S1, Hirata et al. 2015. PubMed ID: 26635368). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD.. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
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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Hereditary cancer-predisposing syndrome Uncertain:1
The p.A1202S variant (also known as c.3604G>T), located in coding exon 27 of the NF1 gene, results from a G to T substitution at nucleotide position 3604. The alanine at codon 1202 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a series of suspected neurofibromatosis type 1 patients; however, detailed clinical information was not presented (Griffiths S et al. Fam. Cancer 2007;6(1):21-34). This variant was previously reported in the SNPDatabase as rs146641724. Based on data from the NHLBI Exome Sequencing Project (ESP), the T allele has an overall frequency of approximately 0.02% (2/13006) total alleles studied, having been observed in 0.02% (2/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.008% (greater than 110000 alleles tested) in our clinical cohort. This amino acid position is highly 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.A1202S remains unclear. -
Lymphedema Benign:1
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Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Neurofibromatosis, type 1;C2931482:Neurofibromatosis-Noonan syndrome Other:1
Variant classified as Uncertain significance and reported on 02-15-2021 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at