Genetic Variant FANCD2:c.1099-107G>T (chr3-10043722-G-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001018115.3(FANCD2):c.1099-107G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0061 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0076 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

FANCD2
NM_001018115.3 intron

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.628

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3 link	c.1099-107G>T		intron_variant	Intron 13 of 43	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.1099-107G>T		intron_variant	Intron 13 of 43		NM_001018115.3	ENSP00000502379.1		Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

792

AN:

130220

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0101

Gnomad AMI

AF:

0.00865

Gnomad AMR

AF:

0.00734

Gnomad ASJ

AF:

0.00164

Gnomad EAS

AF:

0.00260

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00493

Gnomad MID

AF:

0.00368

Gnomad NFE

AF:

0.00373

Gnomad OTH

AF:

0.00437

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00757

AC:

7359

AN:

972122

Hom.:

Cov.:

AF XY:

0.00809

AC XY:

3996

AN XY:

493720

show subpopulations

Gnomad4 AFR exome

AF:

0.00869

Gnomad4 AMR exome

AF:

0.00835

Gnomad4 ASJ exome

AF:

0.00649

Gnomad4 EAS exome

AF:

0.00501

Gnomad4 SAS exome

AF:

0.0120

Gnomad4 FIN exome

AF:

0.00332

Gnomad4 NFE exome

AF:

0.00756

Gnomad4 OTH exome

AF:

0.00634

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00610

AC:

795

AN:

130334

Hom.:

Cov.:

AF XY:

0.00619

AC XY:

396

AN XY:

63974

show subpopulations

Gnomad4 AFR

AF:

0.0101

Gnomad4 AMR

AF:

0.00733

Gnomad4 ASJ

AF:

0.00164

Gnomad4 EAS

AF:

0.00261

Gnomad4 SAS

AF:

0.0111

Gnomad4 FIN

AF:

0.00493

Gnomad4 NFE

AF:

0.00374

Gnomad4 OTH

AF:

0.00431

Alfa

AF:

0.0141

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 29, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.15

DANN

Benign

0.70

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over