rs35782247

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001018115.3(FANCD2):ā€‹c.1367T>Gā€‹(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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā˜…ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L456I) has been classified as Uncertain significance.

Frequency

Genomes: š‘“ 0.027 ( 6 hom., cov: 45)
Exomes š‘“: 0.0027 ( 3 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

5
13

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12O:1

Conservation

PhyloP100: 3.53
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0034121275).
BP6
Variant 3-10048005-T-G is Benign according to our data. Variant chr3-10048005-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 134311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10048005-T-G is described in Lovd as [Benign]. Variant chr3-10048005-T-G is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FANCD2NM_001018115.3 linkuse as main transcriptc.1367T>G p.Leu456Arg missense_variant 16/44 ENST00000675286.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FANCD2ENST00000675286.1 linkuse as main transcriptc.1367T>G p.Leu456Arg missense_variant 16/44 NM_001018115.3 P2Q9BXW9-2

Frequencies

GnomAD3 genomes
AF:
0.0269
AC:
4080
AN:
151728
Hom.:
7
Cov.:
45
show subpopulations
Gnomad AFR
AF:
0.0943
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0101
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000620
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000220
Gnomad OTH
AF:
0.0225
GnomAD3 exomes
AF:
0.00705
AC:
1772
AN:
251396
Hom.:
2
AF XY:
0.00518
AC XY:
704
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.0988
Gnomad AMR exome
AF:
0.00382
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000202
Gnomad OTH exome
AF:
0.00277
GnomAD4 exome
AF:
0.00268
AC:
3921
AN:
1461310
Hom.:
3
Cov.:
63
AF XY:
0.00235
AC XY:
1712
AN XY:
726998
show subpopulations
Gnomad4 AFR exome
AF:
0.0945
Gnomad4 AMR exome
AF:
0.00447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000580
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000125
Gnomad4 OTH exome
AF:
0.00713
GnomAD4 genome
AF:
0.0269
AC:
4086
AN:
151846
Hom.:
6
Cov.:
45
AF XY:
0.0264
AC XY:
1964
AN XY:
74262
show subpopulations
Gnomad4 AFR
AF:
0.0942
Gnomad4 AMR
AF:
0.0101
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000220
Gnomad4 OTH
AF:
0.0222
Alfa
AF:
0.00592
Hom.:
1
ESP6500AA
AF:
0.104
AC:
458
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00874
AC:
1061
Asia WGS
AF:
0.00982
AC:
34
AN:
3478
EpiCase
AF:
0.000109
EpiControl
AF:
0.000237

ClinVar

Significance: Benign/Likely benign
Submissions summary: Pathogenic:1Benign:12Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, Amsterdam University Medical Center-- -
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 20, 2021Variant 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. -
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesMar 29, 2017- -
Fanconi anemia complementation group D2 Pathogenic:1Benign:2
Pathogenic, flagged submissioncurationLeiden Open Variation DatabaseFeb 28, 2020Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxApr 25, 2019This variant is associated with the following publications: (PMID: 21356188, 27153395, 24728327, 20981092, 17436244) -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Benign, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsDec 14, 2016- -
Fanconi anemia Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeDec 07, 2023- -
Benign, criteria provided, single submittercurationSema4, Sema4Sep 10, 2020- -
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
0.0056
T
BayesDel_noAF
Benign
-0.23
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.071
.;T;T
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.50
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.78
T;T;.
MetaRNN
Benign
0.0034
T;T;T
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.6
M;M;M
MutationTaster
Benign
0.89
N;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.99
N;N;N
REVEL
Benign
0.24
Sift
Benign
0.32
T;T;T
Sift4G
Benign
0.35
T;T;T
Polyphen
1.0
.;D;D
Vest4
0.81
MVP
0.84
MPC
0.48
ClinPred
0.025
T
GERP RS
5.7
Varity_R
0.34
gMVP
0.51

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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: rs35782247; hg19: chr3-10089689; COSMIC: COSV55034964; COSMIC: COSV55034964; API