Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001018115.3(FANCD2):c.1122A>G(p.Val374Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 151,510 control chromosomes in the GnomAD database, including 236 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.19 ( 236 hom., cov: 34)

Exomes 𝑓: 0.10 ( 155 hom. )

Failed GnomAD Quality Control

Consequence

FANCD2
NM_001018115.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.0460

Publications

14 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 3-10043852-A-G is Benign according to our data. Variant chr3-10043852-A-G is described in ClinVar as Benign. ClinVar VariationId is 257065.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.046 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

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
FANCD2	NM_001018115.3	MANE Select	c.1122A>G	p.Val374Val	synonymous	Exon 14 of 44	NP_001018125.1
FANCD2	NM_033084.6		c.1122A>G	p.Val374Val	synonymous	Exon 14 of 43	NP_149075.2
FANCD2	NM_001374254.1		c.1122A>G	p.Val374Val	synonymous	Exon 14 of 42	NP_001361183.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCD2	ENST00000675286.1	MANE Select	c.1122A>G	p.Val374Val	synonymous	Exon 14 of 44	ENSP00000502379.1
FANCD2	ENST00000287647.7	TSL:1	c.1122A>G	p.Val374Val	synonymous	Exon 14 of 43	ENSP00000287647.3
FANCD2	ENST00000419585.5	TSL:1	c.1122A>G	p.Val374Val	synonymous	Exon 14 of 44	ENSP00000398754.1

Frequencies

GnomAD3 genomes

AF:

0.193

AC:

29209

AN:

151394

Hom.:

235

Cov.:

show subpopulations

Gnomad AFR

AF:

0.335

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.142

Gnomad EAS

AF:

0.0604

Gnomad SAS

AF:

0.147

Gnomad FIN

AF:

0.108

Gnomad MID

AF:

0.121

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.171

GnomAD2 exomes

AF:

0.0925

AC:

20162

AN:

218080

AF XY:

0.0863

show subpopulations

Gnomad AFR exome

AF:

0.288

Gnomad AMR exome

AF:

0.0988

Gnomad ASJ exome

AF:

0.0838

Gnomad EAS exome

AF:

0.0387

Gnomad FIN exome

AF:

0.0746

Gnomad NFE exome

AF:

0.0796

Gnomad OTH exome

AF:

0.0973

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0998

AC:

128878

AN:

1291182

Hom.:

155

Cov.:

AF XY:

0.102

AC XY:

65695

AN XY:

645390

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.300

AC:

8498

AN:

28282

American (AMR)

AF:

0.123

AC:

5179

AN:

42062

Ashkenazi Jewish (ASJ)

AF:

0.117

AC:

2847

AN:

24408

East Asian (EAS)

AF:

0.0471

AC:

1839

AN:

39080

South Asian (SAS)

AF:

0.131

AC:

10399

AN:

79614

European-Finnish (FIN)

AF:

0.107

AC:

5550

AN:

52076

Middle Eastern (MID)

AF:

0.121

AC:

652

AN:

5372

European-Non Finnish (NFE)

AF:

0.0906

AC:

87485

AN:

965418

Other (OTH)

AF:

0.117

AC:

6429

AN:

54870

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.347

Heterozygous variant carriers

6310

12620

18929

25239

31549

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2512

5024

7536

10048

12560

<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:

0.193

AC:

29240

AN:

151510

Hom.:

236

Cov.:

AF XY:

0.188

AC XY:

13895

AN XY:

74088

show subpopulations

African (AFR)

AF:

0.335

AC:

13785

AN:

41112

American (AMR)

AF:

0.141

AC:

2143

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

490

AN:

3462

East Asian (EAS)

AF:

0.0603

AC:

312

AN:

5172

South Asian (SAS)

AF:

0.148

AC:

709

AN:

4800

European-Finnish (FIN)

AF:

0.108

AC:

1144

AN:

10580

Middle Eastern (MID)

AF:

0.113

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.148

AC:

10051

AN:

67836

Other (OTH)

AF:

0.170

AC:

359

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

1168

2336

3504

4672

5840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

340

680

1020

1360

1700

<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:

0.170

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Fanconi anemia complementation group D2 (2)

not provided (2)

Fanconi anemia (1)

Fanconi anemia complementation group A (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

1.2

(source)

DANN

Benign

0.58

PhyloP100

-0.046

Mutation Taster

=100/0

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over