rs1801052
Variant summary
Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1
The NM_001042492.3(NF1):c.702G>A(p.Leu234Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.665 in 1,604,776 control chromosomes in the GnomAD database, including 363,710 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L234L) has been classified as Likely benign.
Frequency
Consequence
NM_001042492.3 synonymous
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: Benign. The variant received -21 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NF1 | NM_001042492.3 | c.702G>A | p.Leu234Leu | synonymous_variant | Exon 7 of 58 | ENST00000358273.9 | NP_001035957.1 | |
| NF1 | NM_000267.4 | c.702G>A | p.Leu234Leu | synonymous_variant | Exon 7 of 57 | NP_000258.1 | ||
| NF1 | NM_001128147.3 | c.702G>A | p.Leu234Leu | synonymous_variant | Exon 7 of 15 | NP_001121619.1 |
Ensembl
Frequencies
GnomAD3 genomes 0.572 AC: 86258AN: 150814Hom.: 26990 Cov.: 29 show subpopulations
GnomAD2 exomes AF: 0.627 AC: 157498AN: 251116 AF XY: 0.643 show subpopulations
GnomAD4 exome AF: 0.675 AC: 981504AN: 1453854Hom.: 336713 Cov.: 37 AF XY: 0.676 AC XY: 489500AN XY: 723658 show subpopulations
Age Distribution
GnomAD4 genome 0.572 AC: 86299AN: 150922Hom.: 26997 Cov.: 29 AF XY: 0.568 AC XY: 41858AN XY: 73630 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:7
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This is a RefSeq error. The reference base (c.702G) is the minor allele. The c.7 02A allele has been identified in 70% (46585/66678) of European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org, dbSNP rs1 801052) and thus meets criteria to be classified as benign. -
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Neurofibromatosis, type 1 Benign:4
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
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not provided Benign:3
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Variant summary: The NF1 c.702G>A (p.Leu234Leu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant and 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 75516/121252 control chromosomes (24613 homozygotes) at a frequency of 0.6228021, signifying it is the common allele in the population and is thus a benign polymorphism. In addition, one clinical diagnostic laboratories has classified this variant as benign. Taken together, this variant is classified as benign. -
Neurofibromatosis, familial spinal Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Hereditary cancer-predisposing syndrome Benign:2
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This alteration is classified as benign based on a combination of the following: 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-Noonan syndrome Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Café-au-lait macules with pulmonary stenosis Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Hereditary cancer-predisposing syndrome;CN230736:Cardiovascular phenotype Benign:1
This alteration is classified as 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at