rs766567785
Positions:
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
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )
Consequence
FANCD2
NM_001018115.3 missense
NM_001018115.3 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 9.54
Genes affected
FANCD2 (HGNC:3585): (FA complementation group D2) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.959
PP5
Variant 3-10067267-G-A is Pathogenic according to our data. Variant chr3-10067267-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 241735.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10067267-G-A is described in Lovd as [Pathogenic]. Variant chr3-10067267-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
FANCD2 | NM_001018115.3 | c.2444G>A | p.Arg815Gln | missense_variant | 26/44 | ENST00000675286.1 | NP_001018125.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
FANCD2 | ENST00000675286.1 | c.2444G>A | p.Arg815Gln | missense_variant | 26/44 | NM_001018115.3 | ENSP00000502379 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000131 AC: 33AN: 251202Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135770
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GnomAD4 exome AF: 0.0000623 AC: 91AN: 1461530Hom.: 0 Cov.: 30 AF XY: 0.0000550 AC XY: 40AN XY: 727086
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GnomAD4 genome AF: 0.0000329 AC: 5AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74306
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fanconi anemia complementation group D2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 04, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. - |
Fanconi anemia Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | 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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 02, 2023 | 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. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2024 | 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
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 29, 2024 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M;M
MutationTaster
Benign
D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;D
Vest4
MutPred
Gain of methylation at K817 (P = 0.0897);Gain of methylation at K817 (P = 0.0897);Gain of methylation at K817 (P = 0.0897);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at