rs747253294

Variant names:

• chr2-58161532-CATA-C
• rs747253294
• NM_018062.4:c.1007_1009delTAT

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PS3 PM4_Supporting PP5 BS1_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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:11 U:6
• Conservation: PhyloP100: 8.61
• Publications: 4 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: 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

Sel.	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

Sel.	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: 50 AN: 151846 Hom.: 0 Cov.: 32

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: 77 AN: 250564 AF XY: 0.000325

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.: 0 AF XY: 0.000555 AC XY: 399 AN XY: 719070

African (AFR) AF: 0.000121 AC: 4 AN: 32934

American (AMR) AF: 0.0000896 AC: 4 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39484

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85842

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53382

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5722

European-Non Finnish (NFE) AF: 0.000679 AC: 744 AN: 1095338

Other (OTH) AF: 0.00100 AC: 60 AN: 59746

GnomAD4 genome AF: 0.000329 AC: 50 AN: 151846 Hom.: 0 Cov.: 32 AF XY: 0.000324 AC XY: 24 AN XY: 74158

African (AFR) AF: 0.000169 AC: 7 AN: 41394

American (AMR) AF: 0.0000657 AC: 1 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000604 AC: 41 AN: 67840

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.000695 Hom.: 0

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

Pathogenic	VUS	Benign	Condition
7	1	-	Fanconi anemia complementation group L (8)
3	1	-	not provided (4)
1	1	-	Fanconi anemia (2)
-	1	-	FANCL-related disorder (1)
-	1	-	not specified (1)
-	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)

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

Other links and lift over

dbSNP: rs747253294; hg19: chr2-58388667;