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

Genomes: 𝑓 0.027 ( 6 hom., cov: 45)
Exomes 𝑓: 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:13O: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 was made for transcript

Our verdict: Benign. The variant received -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 rank MANE Protein UniProt
FANCD2NM_001018115.3 linkc.1367T>G p.Leu456Arg missense_variant Exon 16 of 44 ENST00000675286.1 NP_001018125.1 Q9BXW9-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
FANCD2ENST00000675286.1 linkc.1367T>G p.Leu456Arg missense_variant Exon 16 of 44 NM_001018115.3 ENSP00000502379.1 Q9BXW9-2

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
GnomAD2 exomes
AF:
0.00705
AC:
1772
AN:
251396
AF XY:
0.00518
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 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
AC:
3124
AN:
33072
Gnomad4 AMR exome
AF:
0.00447
AC:
200
AN:
44702
Gnomad4 ASJ exome
AF:
0.00
AC:
0
AN:
26130
Gnomad4 EAS exome
AF:
0.00
AC:
0
AN:
39692
Gnomad4 SAS exome
AF:
0.0000580
AC:
5
AN:
86254
Gnomad4 FIN exome
AF:
0.00
AC:
0
AN:
53414
Gnomad4 NFE exome
AF:
0.000125
AC:
139
AN:
1111976
Gnomad4 Remaining exome
AF:
0.00713
AC:
430
AN:
60344
Heterozygous variant carriers
0
251
503
754
1006
1257
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
104
208
312
416
520
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
AC:
0.0942022
AN:
0.0942022
Gnomad4 AMR
AF:
0.0101
AC:
0.0101281
AN:
0.0101281
Gnomad4 ASJ
AF:
0.00
AC:
0
AN:
0
Gnomad4 EAS
AF:
0.00
AC:
0
AN:
0
Gnomad4 SAS
AF:
0.000414
AC:
0.000413907
AN:
0.000413907
Gnomad4 FIN
AF:
0.00
AC:
0
AN:
0
Gnomad4 NFE
AF:
0.000220
AC:
0.000220439
AN:
0.000220439
Gnomad4 OTH
AF:
0.0222
AC:
0.0222327
AN:
0.0222327
Heterozygous variant carriers
0
236
472
709
945
1181
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Variant carriers
0
40
80
120
160
200
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00690
Hom.:
4
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:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Fanconi anemia complementation group D2 Pathogenic:1Benign:3
Sep 12, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Feb 28, 2020
Leiden Open Variation Database
Significance:Pathogenic
Review Status:flagged submission
Collection Method:curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach. -

not provided Benign:4
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Dec 14, 2016
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 25, 2019
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 21356188, 27153395, 24728327, 20981092, 17436244) -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

not specified Benign:3Other:1
-
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Sep 19, 2013
ITMI
Significance:not provided
Review Status:no classification provided
Collection Method:reference population

- -

Dec 20, 2021
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Sep 10, 2020
Sema4, Sema4
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Oct 21, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:1
Apr 19, 2022
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

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
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
Mutation Taster
=98/2
polymorphism (auto)

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; API