rs766567785
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001018115.3(FANCD2):c.2444G>A(p.Arg815Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000595 in 1,613,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_001018115.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000131 AC: 33AN: 251202Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135770
GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461530Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727086
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306
ClinVar
Submissions by phenotype
Fanconi anemia complementation group D2 Pathogenic:5
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Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
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Fanconi anemia Pathogenic:2
Variant summary: FANCD2 c.2444G>A (p.Arg815Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251202 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in FANCD2 causing Fanconi Anemia (0.00013 vs 0.00048), allowing no conclusion about variant significance. c.2444G>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Fanconi Anemia and was shown to segregate with disease within at least one family (Kalb_2007, Esmail Nia_2016). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 815 of the FANCD2 protein (p.Arg815Gln). This variant is present in population databases (rs766567785, gnomAD 0.05%). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 17436244, 27041517). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 241735). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FANCD2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27795557, 31589614, Chan2021[article], 30713837, 17436244, 32191290, 34308104, 35417938, 35725860, 27041517) -
FANCD2-related disorder Pathogenic:1
The FANCD2 c.2444G>A variant is predicted to result in the amino acid substitution p.Arg815Gln. This variant has been reported in the homozygous or compound heterozygous state in several patients with Fanconi anemia (Kalb et al 2007. PubMed ID: 17436244; Esmail et al. 2016. PubMed ID: 27041517; Deniskin et al. 2018. PubMed ID: 30713837). This variant has also been reported along with a second variant in FANCD2 in two individuals with osteosarcoma (eTable 5, Mirabello et al. 2020. PubMed ID: 32191290). This variant is reported in 0.058% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at