rs1553608861

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The ENST00000287647.7(FANCD2):​c.1278+1_1278+2insT variant causes a splice donor, 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 ENST00000287647.7 splice_donor, 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 4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.032608695 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000287647.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.1278+2dupT		splice_region intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.1278+2dupT		splice_region intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.1278+2dupT		splice_region intron	N/A	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.1278+1_1278+2insT		splice_donor intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.1278+1_1278+2insT		splice_donor intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.1278+1_1278+2insT		splice_donor intron	N/A	ENSP00000398754.1

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

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;