2-58160147-ACT-ACTCT

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_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 (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

FANCL
NM_018062.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.25

Publications

3 publications found

Variant links:

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 links:

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]

VRK2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 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.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
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

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
FANCL	ENST00000233741.9	TSL:1 MANE Select	c.1051_1052dupAG	p.Ser351ArgfsTer19	frameshift	Exon 13 of 14	ENSP00000233741.5
FANCL	ENST00000403295.8	TSL:1	c.967_968dupAG	p.Ser323ArgfsTer19	frameshift	Exon 12 of 13	ENSP00000386097.3
FANCL	ENST00000449070.6	TSL:1	c.874_875dupAG	p.Ser292ArgfsTer19	frameshift	Exon 10 of 11	ENSP00000401280.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250738

AF XY:

0.00000738

show subpopulations

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:

AN:

1460790

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726722

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39564

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111232

Other (OTH)

AF:

0.00

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia

Pathogenic:1

Apr 16, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: FANCL c.1051_1052dupAG (p.Ser351ArgfsX19) results in a premature termination codon, not anticipated to result in nonsense mediated decay, but predicted to cause a truncation of the encoded protein, disrupting the last 25 amino acids of the FANCL protein. This truncation is expected to remove two conserved, metal ion binding Cys residues that are part of the RING-type Zinc finger domain of the FANCL protein (amino acids 307 - 365; UniProt). This C-terminal domain is necessary for monoubiquitination of FANCD2 (see e.g. PMID 32048394). The variant allele was found at a frequency of 4e-06 in 250738 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1051_1052dupAG in individuals affected with Fanconi Anemia and no experimental evidence demonstrating its impact on protein function have been reported. However, a downstream truncation variant (c.1096_1099dupATTA (p.Thr367AsnfsX13)), has been reported in the literature in a compound heterozygous patient with milder features of Fanconi anemia (FA), and functional studies suggested that this variant results in a partial loss of FANCL activity, indicating a hypomorphic effect for the variant; this study also demonstrated that the variant found on the opposite allele (in trans) in this patient was a functionally null mutation (PMID 19405097). On the other hand, the variant, c.1095_1098dupAATT, was also reported t in several homozygous control individuals in the gnomAD database, suggesting that this variant might not be sufficient to cause FA phenotype in homozygous state. 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). Based on their findings, authors proposed haploinsufficiency as a potential causative mechanism for the (provisional) POI phenotype. Other functional studies have shown that Cys 357 is essential for FANCL ubiquitin ligase activity (PMID: 19111657, 17938197). These findings demonstrate that this region of FANCL is critically important to protein function and a disruption is likely to cause disease. ClinVar contains an entry for this variant (Variation ID: 1027625). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Fanconi anemia complementation group L

Pathogenic:1

Apr 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.3

Mutation Taster

=3/197

disease causing

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over