chr2-58229882-T-C

Variant names:

• chr2-58229882-T-C
• rs878855045
• NM_018062.4:c.156-8A>G

Variant summary

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

The NM_018062.4(FANCL):​c.156-8A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCL NM_018062.4 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.00
• Publications: 0 publications found

Genes affected

FANCL (HGNC:20748): (FA complementation group L) This gene encodes a ubiquitin ligase that is a member of the Fanconi anemia complementation group (FANC). Members of this group are related by their assembly into a common nuclear protein complex rather than by sequence similarity. This gene encodes the protein for complementation group L that mediates monoubiquitination of FANCD2 as well as FANCI. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2018]

FANCL Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group L

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• 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: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018062.4. 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
	FANCL	NM_018062.4	MANE Select	c.156-8A>G		splice_region intron	N/A	NP_060532.2
	FANCL	NM_001438889.1		c.156-8A>G		splice_region intron	N/A	NP_001425818.1
	FANCL	NM_001410792.1		c.156-8A>G		splice_region intron	N/A	NP_001397721.1	A0A8Q3SIK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.156-8A>G		splice_region intron	N/A	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000403295.8	TSL:1	c.156-8A>G		splice_region intron	N/A	ENSP00000386097.3	B5MC31
	FANCL	ENST00000449070.6	TSL:1	c.97-7840A>G		intron	N/A	ENSP00000401280.2	C9JZA9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Benign	0.90
PhyloP100		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.91		Position offset: -1
DS_AL_spliceai		0.65		Position offset: -8

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

Other links and lift over

dbSNP: rs878855045; hg19: chr2-58457017;