rs41281511

Positions:

• chr2-58241352-T-C
• chr2-58241352-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000449070.6(FANCL):​c.-39A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000878 in 1,594,122 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00057 (3 hom.)
• Consequence: FANCL ENST00000449070.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.969

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-58241352-T-C is Benign according to our data. Variant chr2-58241352-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 257492.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000569 (821/1441740) while in subpopulation AFR AF= 0.0137 (454/33032). AF 95% confidence interval is 0.0127. There are 3 homozygotes in gnomad4_exome. There are 371 alleles in male gnomad4_exome subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCL	NM_018062.4			upstream_gene_variant		ENST00000233741.9	NP_060532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
	ENST00000608934.1	n.4T>C		non_coding_transcript_exon_variant	1/1
FANCL	ENST00000233741.9			upstream_gene_variant		1	NM_018062.4	ENSP00000233741	P4

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152264 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00127 AC: 298 AN: 235150 Hom.: 1 AF XY: 0.000947 AC XY: 121 AN XY: 127838

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00103

Gnomad EAS exome AF: 0.000516

Gnomad SAS exome AF: 0.0000336

Gnomad FIN exome AF: 0.0000528

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.000517

GnomAD4 exome AF: 0.000569 AC: 821 AN: 1441740 Hom.: 3 Cov.: 26 AF XY: 0.000517 AC XY: 371 AN XY: 717978

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00100

Gnomad4 EAS exome AF: 0.000380

Gnomad4 SAS exome AF: 0.0000936

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00379 AC: 578 AN: 152382 Hom.: 5 Cov.: 33 AF XY: 0.00376 AC XY: 280 AN XY: 74528

Gnomad4 AFR AF: 0.0125

Gnomad4 AMR AF: 0.00189

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.00419

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 24, 2019

- -

Fanconi anemia complementation group L Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.2
DANN	Benign	0.42

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs41281511; hg19: chr2-58468487;