Genetic Variant FANCL:p.Ile336_Cys337delinsSer (chr2-58161532-CATA-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3PM4_SupportingPP5BS1_Supporting

The NM_018062.4(FANCL):c.1007_1009delTAT(p.Ile336_Cys337delinsSer) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,594,924 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000966835: "In vitro functional studies, including a complementation assay, support an impact on protein function (Ali 2009)."" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00057 ( 0 hom. )

Consequence

FANCL
NM_018062.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11U:6

Conservation

PhyloP100: 8.61

Publications

4 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: Uncertain_significance. The variant received 5 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000966835: "In vitro functional studies, including a complementation assay, support an impact on protein function (Ali 2009)."; SCV000568796: Published functional studies demonstrate a damaging effect: studies in EUFA868 cells showed this allele resulted in substantial G2/M arrest, lack of FANCD2 monoubiquitination, increased sensitivity to mitomycin C, and a high rate of chromosome breakage (PMID: 19405097); SCV000914933: Expression of the variant protein in a cell line lacking the FANCL protein was unable to rescue the phenotype of G2/M arrest, absent mono-ubiquitination with FANCD2, increased sensitivity to mitomycin C and a high rate of chromosome breakage, suggesting the variant impairs protein function (Ali et al. 2009).; SCV002495757: In vitro functional studies predict that this variant will impact the protein (Ali 2009 PMID:19405097).; SCV004197257: Experimental studies demonstrated that this variant impact the protein function (PMID: 19405097, 25659033).; SCV005438722: Experimental studies have shown that this variant affects FANCL function Ali et. al., 2009.

PM4

Nonframeshift variant in NON repetitive region in NM_018062.4. Strenght limited to Supporting due to length of the change: 1aa.

PP5

Variant 2-58161532-CATA-C is Pathogenic according to our data. Variant chr2-58161532-CATA-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241247.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000329 (50/151846) while in subpopulation NFE AF = 0.000604 (41/67840). AF 95% confidence interval is 0.000458. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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	UniProt
FANCL	NM_018062.4	MANE Select	c.1007_1009delTAT	p.Ile336_Cys337delinsSer	disruptive_inframe_deletion	Exon 12 of 14	NP_060532.2
FANCL	NM_001438889.1		c.1052_1054delTAT	p.Ile351_Cys352delinsSer	disruptive_inframe_deletion	Exon 13 of 14	NP_001425818.1
FANCL	NM_001410792.1		c.1067_1069delTAT	p.Ile356_Cys357delinsSer	disruptive_inframe_deletion	Exon 13 of 15	NP_001397721.1	A0A8Q3SIK5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FANCL	ENST00000233741.9	TSL:1 MANE Select	c.1007_1009delTAT	p.Ile336_Cys337delinsSer	disruptive_inframe_deletion	Exon 12 of 14	ENSP00000233741.5	Q9NW38-1
FANCL	ENST00000403295.8	TSL:1	c.923_925delTAT	p.Ile308_Cys309delinsSer	disruptive_inframe_deletion	Exon 11 of 13	ENSP00000386097.3	B5MC31
FANCL	ENST00000449070.6	TSL:1	c.830_832delTAT	p.Ile277_Cys278delinsSer	disruptive_inframe_deletion	Exon 9 of 11	ENSP00000401280.2	C9JZA9

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

151846

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000604

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.000307

AC:

AN:

250564

AF XY:

0.000325

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000619

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000566

AC:

817

AN:

1443078

Hom.:

AF XY:

0.000555

AC XY:

399

AN XY:

719070

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

32934

American (AMR)

AF:

0.0000896

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25976

East Asian (EAS)

AF:

0.00

AC:

AN:

39484

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85842

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53382

Middle Eastern (MID)

AF:

0.000350

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.000679

AC:

744

AN:

1095338

Other (OTH)

AF:

0.00100

AC:

AN:

59746

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.433

Heterozygous variant carriers

124

165

206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000329

AC:

AN:

151846

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41394

American (AMR)

AF:

0.0000657

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000604

AC:

AN:

67840

Other (OTH)

AF:

0.000480

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000695

Hom.:

Bravo

AF:

0.000298

EpiCase

AF:

0.000873

EpiControl

AF:

0.000949

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Fanconi anemia complementation group L (8)

not provided (4)

Fanconi anemia (2)

FANCL-related disorder (1)

not specified (1)

Premature ovarian insufficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

8.6

Mutation Taster

=5/195

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over