chr3-10062161-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001018115.3(FANCD2):c.1777C>T(p.Pro593Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00108 in 1,611,616 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00073 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 2 hom. )

Consequence

FANCD2
NM_001018115.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:4O:1

Conservation

PhyloP100: 0.393

Publications

8 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006657213).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018115.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCD2	NM_001018115.3	MANE Select	c.1777C>T	p.Pro593Ser	missense	Exon 20 of 44	NP_001018125.1	Q9BXW9-2
FANCD2	NM_033084.6		c.1777C>T	p.Pro593Ser	missense	Exon 20 of 43	NP_149075.2
FANCD2	NM_001374254.1		c.1777C>T	p.Pro593Ser	missense	Exon 20 of 42	NP_001361183.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCD2	ENST00000675286.1	MANE Select	c.1777C>T	p.Pro593Ser	missense	Exon 20 of 44	ENSP00000502379.1	Q9BXW9-2
FANCD2	ENST00000287647.7	TSL:1	c.1777C>T	p.Pro593Ser	missense	Exon 20 of 43	ENSP00000287647.3	Q9BXW9-1
FANCD2	ENST00000419585.5	TSL:1	c.1777C>T	p.Pro593Ser	missense	Exon 20 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.000730

AC:

111

AN:

151974

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.00645

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000883

AC:

222

AN:

251280

AF XY:

0.000935

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000666

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00111

AC:

1627

AN:

1459540

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

788

AN XY:

726058

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33406

American (AMR)

AF:

0.000784

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.000456

AC:

AN:

85600

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.00130

AC:

1445

AN:

1110686

Other (OTH)

AF:

0.00118

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

151

226

302

377

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.000730

AC:

111

AN:

152076

Hom.:

Cov.:

AF XY:

0.000646

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41504

American (AMR)

AF:

0.000524

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000623

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00694

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

68010

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00123

Hom.:

Bravo

AF:

0.000805

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000964

AC:

117

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00186

EpiControl

AF:

0.00184

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia complementation group D2 (4)

not provided (4)

Fanconi anemia (2)

FANCD2-related disorder (1)

Hereditary cancer-predisposing syndrome (1)

Malignant tumor of breast (1)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.23

(source)

DANN

Benign

0.56

DEOGEN2

Benign

0.029

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.00045

LIST_S2

Benign

0.33

M_CAP

Benign

0.0062

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.55

PhyloP100

0.39

PrimateAI

Benign

0.29

PROVEAN

Benign

1.6

REVEL

Benign

0.044

Sift

Benign

0.75

Sift4G

Benign

0.67

Polyphen

0.0010

Vest4

0.045

MVP

0.19

MPC

0.15

ClinPred

0.00080

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.012

gMVP

0.058

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over