Genetic Variant FANCD2:p.Thr716Thr (chr3-10064855-C-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001018115.3(FANCD2):c.2148C>G(p.Thr716Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,540 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T716T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0094 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 84 hom. )

Consequence

FANCD2
NM_001018115.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.737

Publications

5 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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 3-10064855-C-G is Benign according to our data. Variant chr3-10064855-C-G is described in ClinVar as Benign. ClinVar VariationId is 241734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.737 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0094 (1432/152286) while in subpopulation NFE AF = 0.0148 (1005/68020). AF 95% confidence interval is 0.014. There are 8 homozygotes in GnomAd4. There are 652 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.2148C>G	p.Thr716Thr	synonymous	Exon 23 of 44	NP_001018125.1	Q9BXW9-2
FANCD2	NM_033084.6		c.2148C>G	p.Thr716Thr	synonymous	Exon 23 of 43	NP_149075.2
FANCD2	NM_001374254.1		c.2148C>G	p.Thr716Thr	synonymous	Exon 23 of 42	NP_001361183.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCD2	ENST00000675286.1	MANE Select	c.2148C>G	p.Thr716Thr	synonymous	Exon 23 of 44	ENSP00000502379.1	Q9BXW9-2
FANCD2	ENST00000287647.7	TSL:1	c.2148C>G	p.Thr716Thr	synonymous	Exon 23 of 43	ENSP00000287647.3	Q9BXW9-1
FANCD2	ENST00000419585.5	TSL:1	c.2148C>G	p.Thr716Thr	synonymous	Exon 23 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.00941

AC:

1432

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00601

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00957

GnomAD2 exomes

AF:

0.00987

AC:

2478

AN:

251072

AF XY:

0.0101

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.00564

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.00996

GnomAD4 exome

AF:

0.0123

AC:

18024

AN:

1461254

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

8929

AN XY:

726998

show subpopulations

African (AFR)

AF:

0.00173

AC:

AN:

33462

American (AMR)

AF:

0.00611

AC:

273

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00980

AC:

256

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00746

AC:

643

AN:

86242

European-Finnish (FIN)

AF:

0.00487

AC:

260

AN:

53418

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0143

AC:

15877

AN:

1111454

Other (OTH)

AF:

0.0107

AC:

648

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

787

1575

2362

3150

3937

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

588

1176

1764

2352

2940

<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:

0.00940

AC:

1432

AN:

152286

Hom.:

Cov.:

AF XY:

0.00875

AC XY:

652

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.00257

AC:

107

AN:

41570

American (AMR)

AF:

0.00706

AC:

108

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00979

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00601

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00255

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0148

AC:

1005

AN:

68020

Other (OTH)

AF:

0.00947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

126

190

253

316

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0119

Hom.:

Bravo

AF:

0.00964

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0138

EpiControl

AF:

0.0144

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia complementation group D2 (2)

not provided (2)

not specified (2)

Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.3

(source)

DANN

Benign

0.37

PhyloP100

-0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=100/0

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