rs79588315

Positions:

• chr2-58226795-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018062.4(FANCL):​c.217-11T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0837 in 1,605,374 control chromosomes in the GnomAD database, including 6,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (408 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5833 hom.)
• Consequence: FANCL NM_018062.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.7185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.73

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-58226795-A-G is Benign according to our data. Variant chr2-58226795-A-G is described in ClinVar as [Benign]. Clinvar id is 257493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCL	NM_018062.4	c.217-11T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000233741.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCL	ENST00000233741.9	c.217-11T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_018062.4	P4

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9826 AN: 152106 Hom.: 408 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.0755

GnomAD3 exomes AF: 0.0678 AC: 16983 AN: 250540 Hom.: 711 AF XY: 0.0691 AC XY: 9354 AN XY: 135388

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0700

Gnomad EAS exome AF: 0.0168

Gnomad SAS exome AF: 0.0391

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0786

GnomAD4 exome AF: 0.0857 AC: 124516 AN: 1453148 Hom.: 5833 Cov.: 30 AF XY: 0.0847 AC XY: 61245 AN XY: 723394

Gnomad4 AFR exome AF: 0.0286

Gnomad4 AMR exome AF: 0.0508

Gnomad4 ASJ exome AF: 0.0711

Gnomad4 EAS exome AF: 0.0275

Gnomad4 SAS exome AF: 0.0422

Gnomad4 FIN exome AF: 0.0642

Gnomad4 NFE exome AF: 0.0958

Gnomad4 OTH exome AF: 0.0860

GnomAD4 genome AF: 0.0645 AC: 9824 AN: 152226 Hom.: 408 Cov.: 32 AF XY: 0.0628 AC XY: 4672 AN XY: 74434

Gnomad4 AFR AF: 0.0297

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.0717

Gnomad4 EAS AF: 0.0212

Gnomad4 SAS AF: 0.0379

Gnomad4 FIN AF: 0.0587

Gnomad4 NFE AF: 0.0921

Gnomad4 OTH AF: 0.0743

Alfa AF: 0.0729 Hom.: 112

Bravo AF: 0.0623

Asia WGS AF: 0.0240 AC: 84 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group L Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 10, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 48
DS_AL_spliceai		0.37		Position offset: -11

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

Publications

LitVar

Other links and lift over

dbSNP: rs79588315; hg19: chr2-58453930; COSMIC: COSV52072784;