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

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000062 ( 0 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

10
8
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.54
Variant links:
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]

Genome browser will be placed here

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
FANCD2NM_001018115.3 linkuse as main transcriptc.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
FANCD2ENST00000675286.1 linkuse as main transcriptc.2444G>A p.Arg815Gln missense_variant 26/44 NM_001018115.3 ENSP00000502379 P2Q9BXW9-2

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000131
AC:
33
AN:
251202
Hom.:
0
AF XY:
0.000118
AC XY:
16
AN XY:
135770
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000880
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.0000623
AC:
91
AN:
1461530
Hom.:
0
Cov.:
30
AF XY:
0.0000550
AC XY:
40
AN XY:
727086
show subpopulations
Gnomad4 AFR exome
AF:
0.0000598
Gnomad4 AMR exome
AF:
0.000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000504
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74306
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000665
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.000140
AC:
17
EpiCase
AF:
0.0000545
EpiControl
AF:
0.000119

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 submitterclinical testingRevvity Omics, RevvityFeb 04, 2019- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 27, 2024- -
Pathogenic, no assertion criteria providedcurationLeiden Open Variation DatabaseFeb 28, 2020Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Fanconi anemia Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 21, 2023This 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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 02, 2023Variant 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 submitterclinical testingGeneDxSep 22, 2024In 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 providedclinical testingPreventionGenetics, part of Exact SciencesMay 29, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.65
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
29
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.51
.;D;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;.
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.96
D;D;D
MetaSVM
Uncertain
-0.046
T
MutationAssessor
Uncertain
2.8
M;M;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Uncertain
-3.9
D;D;D
REVEL
Pathogenic
0.74
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
.;D;D
Vest4
0.98
MutPred
0.84
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
0.89
MPC
0.68
ClinPred
0.92
D
GERP RS
5.4
Varity_R
0.90
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs766567785; hg19: chr3-10108951; API