7-140781711-A-C
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_004333.6(BRAF):c.1315-18T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,603,110 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_004333.6 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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BRAF | ENST00000644969.2 | c.1435-18T>G | intron_variant | Intron 11 of 19 | NM_001374258.1 | ENSP00000496776.1 | ||||
BRAF | ENST00000646891.2 | c.1315-18T>G | intron_variant | Intron 10 of 17 | NM_004333.6 | ENSP00000493543.1 |
Frequencies
GnomAD3 genomes AF: 0.00763 AC: 1160AN: 152090Hom.: 18 Cov.: 32
GnomAD3 exomes AF: 0.00200 AC: 502AN: 251252Hom.: 4 AF XY: 0.00150 AC XY: 204AN XY: 135796
GnomAD4 exome AF: 0.000819 AC: 1189AN: 1450902Hom.: 12 Cov.: 27 AF XY: 0.000715 AC XY: 517AN XY: 722714
GnomAD4 genome AF: 0.00763 AC: 1161AN: 152208Hom.: 18 Cov.: 32 AF XY: 0.00754 AC XY: 561AN XY: 74412
ClinVar
Submissions by phenotype
not specified Benign:6
Variant summary: BRAF c.1315-18T>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.002 in 251252 control chromosomes, predominantly at a frequency of 0.028 within the African or African-American subpopulation in the gnomAD database, including 4 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 11200-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRAF causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1315-18T>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign. Based on the evidence outlined above, the variant was 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. -
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Lung cancer;C0346629:Colorectal cancer;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C3150970:Noonan syndrome 7;C3150971:LEOPARD syndrome 3;C4551602:Noonan syndrome 1;CN029449:Cardiofaciocutaneous syndrome 1 Benign:1
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not provided Benign:1
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RASopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at