chr3-10046724-G-GT

Variant names:

• chr3-10046724-G-GT
• rs1553608861
• NM_001018115.3:c.1278+2dupT

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001018115.3(FANCD2):​c.1278+2dupT variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 46)
  • Exomes 𝑓: 0.0000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.06
• Publications: 0 publications found

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1278+2dupT		splice_region_variant, intron_variant	Intron 15 of 43	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1278+1_1278+2insT		splice_donor_variant, intron_variant	Intron 15 of 43		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes Cov.: 46

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000378 AC: 1 AN: 264222 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 137390

African (AFR) AF: 0.00 AC: 0 AN: 4882

American (AMR) AF: 0.00 AC: 0 AN: 18284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5992

East Asian (EAS) AF: 0.00 AC: 0 AN: 13090

South Asian (SAS) AF: 0.00 AC: 0 AN: 35328

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 996

European-Non Finnish (NFE) AF: 0.00000599 AC: 1 AN: 166884

Other (OTH) AF: 0.00 AC: 0 AN: 11256

GnomAD4 genome Cov.: 46

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Oct 13, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 15 of the FANCD2 gene. It does not directly change the encoded amino acid sequence of the FANCD2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with FANCD2-related disease. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: -1

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

Other links and lift over

dbSNP: rs1553608861; hg19: chr3-10088408;