rs35782247
Variant summary
Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001018115.3(FANCD2):c.1367T>G(p.Leu456Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00496 in 1,613,156 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L456I) has been classified as Uncertain significance.
Frequency
Consequence
NM_001018115.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Benign. The variant received -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0269 AC: 4080AN: 151728Hom.: 7 Cov.: 45 show subpopulations
GnomAD2 exomes AF: 0.00705 AC: 1772AN: 251396 AF XY: 0.00518 show subpopulations
GnomAD4 exome AF: 0.00268 AC: 3921AN: 1461310Hom.: 3 Cov.: 63 AF XY: 0.00235 AC XY: 1712AN XY: 726998 show subpopulations
GnomAD4 genome AF: 0.0269 AC: 4086AN: 151846Hom.: 6 Cov.: 45 AF XY: 0.0264 AC XY: 1964AN XY: 74262 show subpopulations
ClinVar
Submissions by phenotype
Fanconi anemia complementation group D2 Pathogenic:1Benign:3
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This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
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Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
not provided Benign:4
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This variant is associated with the following publications: (PMID: 21356188, 27153395, 24728327, 20981092, 17436244) -
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not specified Benign:3Other:1
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Variant summary: FANCD2 c.1367T>G (p.Leu456Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.007 in 251396 control chromosomes, predominantly at a frequency of 0.099 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 204.49 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCD2 causing Fanconi Anemia phenotype (0.00048), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with conflicting interpretation. Based on the evidence outlined above, the variant was classified as benign. -
Fanconi anemia Benign:2
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Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at