2-58160147-ACT-ACTCT

Variant names:

• chr2-58160147-A-ACT
• rs750871999
• NM_018062.4:c.1051_1052dupAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PM2 PP5_Very_Strong

The NM_018062.4(FANCL):​c.1051_1052dupAG​(p.Ser351ArgfsTer19) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001519534: An overlapping truncation variant (c.1048_1051delCAGA (p.Gln350ValfsX18)), was also described in the literature in a heterozygous patient with premature ovary insufficiency (POI), and authors of this study demonstrated that while the wildtype FANCL protein was predominantly localized in the nuclei, the variant FANCL protein was retained in the cytoplasm, in addition, this variant resulted in loss of ubiquitinligase activity and decreased DNA damage repair capacity (PMID 32048394).".

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCL NM_018062.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.25
• Publications: 3 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]

VRK2 (HGNC:12719): (VRK serine/threonine kinase 2) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. The encoded protein acts as an effector of signaling pathways that regulate apoptosis and tumor cell growth. Variants in this gene have been associated with schizophrenia. Alternative splicing results in multiple transcript variants that differ in their subcellular localization and biological activity. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001519534: An overlapping truncation variant (c.1048_1051delCAGA (p.Gln350ValfsX18)), was also described in the literature in a heterozygous patient with premature ovary insufficiency (POI), and authors of this study demonstrated that while the wildtype FANCL protein was predominantly localized in the nuclei, the variant FANCL protein was retained in the cytoplasm, in addition, this variant resulted in loss of ubiquitinligase activity and decreased DNA damage repair capacity (PMID 32048394).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-58160147-A-ACT is Pathogenic according to our data. Variant chr2-58160147-A-ACT is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1027625.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1051_1052dupAG	p.Ser351ArgfsTer19	frameshift	Exon 13 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.1096_1097dupAG	p.Ser366ArgfsTer16	frameshift	Exon 14 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.1111_1112dupAG	p.Ser371ArgfsTer19	frameshift	Exon 14 of 15	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.1051_1052dupAG	p.Ser351ArgfsTer19	frameshift	Exon 13 of 14	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000403295.8	TSL:1	c.967_968dupAG	p.Ser323ArgfsTer19	frameshift	Exon 12 of 13	ENSP00000386097.3	B5MC31
	FANCL	ENST00000449070.6	TSL:1	c.874_875dupAG	p.Ser292ArgfsTer19	frameshift	Exon 10 of 11	ENSP00000401280.2	C9JZA9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250738 AF XY: 0.00000738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460790 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726722

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39564

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111232

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Fanconi anemia (1)
1	-	-	Fanconi anemia complementation group L (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=3/197	disease causing

Splicing

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

Other links and lift over

dbSNP: rs750871999; hg19: chr2-58387282;