rs759217526

Variant names:

• chr2-58159793-G-GTAAT
• rs759217526
• NM_018062.4:c.1096_1099dupATTA

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_Moderate BS1_Supporting BS2

The NM_018062.4(FANCL):​c.1096_1099dupATTA​(p.Thr367AsnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,612,828 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T367T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (18 hom.)
• Consequence: FANCL NM_018062.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:12 B:5
• Conservation: PhyloP100: 2.00
• Publications: 38 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: Likely_benign. The variant received -3 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0257 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00299 (455/152068) while in subpopulation NFE AF = 0.00422 (287/67940). AF 95% confidence interval is 0.00382. There are 3 homozygotes in GnomAd4. There are 204 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
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.1096_1099dupATTA	p.Thr367AsnfsTer13	frameshift	Exon 14 of 14	NP_060532.2
	VRK2	NM_006296.7	MANE Select	c.*102_*105dupAATT		3_prime_UTR	Exon 13 of 13	NP_006287.2	Q86Y07-1
	FANCL	NM_001410792.1		c.1156_1159dupATTA	p.Thr387AsnfsTer13	frameshift	Exon 15 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.1096_1099dupATTA	p.Thr367AsnfsTer13	frameshift	Exon 14 of 14	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000403295.8	TSL:1	c.1012_1015dupATTA	p.Thr339AsnfsTer13	frameshift	Exon 13 of 13	ENSP00000386097.3	B5MC31
	FANCL	ENST00000449070.6	TSL:1	c.919_922dupATTA	p.Thr308AsnfsTer13	frameshift	Exon 11 of 11	ENSP00000401280.2	C9JZA9

Frequencies

GnomAD3 genomes AF: 0.00299 AC: 455 AN: 151950 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00387

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00265

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00301 AC: 750 AN: 249062 AF XY: 0.00308

Gnomad AFR exome AF: 0.000766

Gnomad AMR exome AF: 0.00535

Gnomad ASJ exome AF: 0.00669

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00181

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00497

GnomAD4 exome AF: 0.00372 AC: 5434 AN: 1460760 Hom.: 18 Cov.: 31 AF XY: 0.00372 AC XY: 2702 AN XY: 726652

African (AFR) AF: 0.000508 AC: 17 AN: 33446

American (AMR) AF: 0.00466 AC: 208 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00789 AC: 206 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.000708 AC: 61 AN: 86164

European-Finnish (FIN) AF: 0.00179 AC: 95 AN: 53116

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5748

European-Non Finnish (NFE) AF: 0.00414 AC: 4605 AN: 1111540

Other (OTH) AF: 0.00381 AC: 230 AN: 60350

GnomAD4 genome AF: 0.00299 AC: 455 AN: 152068 Hom.: 3 Cov.: 32 AF XY: 0.00274 AC XY: 204 AN XY: 74320

African (AFR) AF: 0.000554 AC: 23 AN: 41526

American (AMR) AF: 0.00387 AC: 59 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00265 AC: 28 AN: 10572

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 67940

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00406 Hom.: 0

Bravo AF: 0.00318

EpiCase AF: 0.00415

EpiControl AF: 0.00427

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	6	1	not provided (8)
2	3	-	Fanconi anemia complementation group L (5)
-	1	2	Fanconi anemia (3)
-	1	1	not specified (2)
-	1	-	FANCL-related disorder (1)
-	-	1	Hereditary cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=182/18	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs759217526; hg19: chr2-58386928; COSMIC: COSV52072800; COSMIC: COSV52072800;