2-58181552-C-T

Variant names:

• chr2-58181552-C-T
• rs848282
• NM_018062.4:c.541-15678G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_018062.4(FANCL):​c.541-15678G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.716 in 151,940 control chromosomes in the GnomAD database, including 40,095 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.72 (40095 hom., cov: 32)
• Consequence: FANCL NM_018062.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0670
• Publications: 6 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]

FANCL Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group L

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.896 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4	c.541-15678G>A		intron_variant	Intron 7 of 13	ENST00000233741.9	NP_060532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9	c.541-15678G>A		intron_variant	Intron 7 of 13	1	NM_018062.4	ENSP00000233741.5

Frequencies

GnomAD3 genomes AF: 0.716 AC: 108713 AN: 151822 Hom.: 40037 Cov.: 32

Gnomad AFR AF: 0.903

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.684

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.662

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.662

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.634

Gnomad OTH AF: 0.675

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.716 AC: 108831 AN: 151940 Hom.: 40095 Cov.: 32 AF XY: 0.717 AC XY: 53253 AN XY: 74250

African (AFR) AF: 0.904 AC: 37516 AN: 41518

American (AMR) AF: 0.685 AC: 10435 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1967 AN: 3464

East Asian (EAS) AF: 0.662 AC: 3428 AN: 5182

South Asian (SAS) AF: 0.702 AC: 3383 AN: 4820

European-Finnish (FIN) AF: 0.662 AC: 6981 AN: 10548

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.634 AC: 43024 AN: 67866

Other (OTH) AF: 0.678 AC: 1427 AN: 2104

Alfa AF: 0.660 Hom.: 17247

Bravo AF: 0.724

Asia WGS AF: 0.729 AC: 2532 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	5.0
DANN	Benign	0.57
PhyloP100		-0.067
Mutation Taster		=100/0	polymorphism (auto)

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: rs848282; hg19: chr2-58408687;