Genetic Variant FANCD2:p.Ile104Asn (chr3-10034732-T-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001018115.3(FANCD2):c.311T>A(p.Ile104Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I104V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.41

Publications

4 publications found

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]

FANCD2 Gene-Disease associations (from GenCC):

Fanconi anemia complementation group D2
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FANCD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.782

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.311T>A	p.Ile104Asn	missense_variant	Exon 5 of 44	ENST00000675286.1	NP_001018125.1	Q9BXW9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1 link	c.311T>A	p.Ile104Asn	missense_variant	Exon 5 of 44		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1420486

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702924

African (AFR)

AF:

0.00

AC:

AN:

32694

American (AMR)

AF:

0.00

AC:

AN:

37968

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25418

East Asian (EAS)

AF:

0.00

AC:

AN:

38210

South Asian (SAS)

AF:

0.00

AC:

AN:

81268

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50728

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090638

Other (OTH)

AF:

0.00

AC:

AN:

58806

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;T;T;.

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

D;D;.;D

M_CAP

Benign

0.060

MetaRNN

Pathogenic

0.78

D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.7

M;M;M;M

PhyloP100

5.4

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

0.98, 0.93

.;D;D;P

Vest4

0.78

MutPred

0.33

Gain of disorder (P = 0.0251);Gain of disorder (P = 0.0251);Gain of disorder (P = 0.0251);Gain of disorder (P = 0.0251);

MVP

0.80

MPC

0.81

ClinPred

0.98

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.76

gMVP

0.66

Mutation Taster

=55/45

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over