rs761291501

Positions:

• chr2-58241312-A-C
• chr2-58241312-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_018062.4(FANCL):​c.2T>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FANCL NM_018062.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.14

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 Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_018062.4 (FANCL) was described as [Likely_pathogenic] in ClinVar as 1335392
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-58241312-A-C is Pathogenic according to our data. Variant chr2-58241312-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 862463.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCL	NM_018062.4	c.2T>G	p.Met1?	start_lost	1/14	ENST00000233741.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCL	ENST00000233741.9	c.2T>G	p.Met1?	start_lost	1/14	1	NM_018062.4	P4
	ENST00000608934.1			upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 17, 2023

This sequence change affects the initiator methionine of the FANCL mRNA. The next in-frame methionine is located at codon 74. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individuals with clinical features of FANCL-related conditions (PMID: 33727708; Invitae). ClinVar contains an entry for this variant (Variation ID: 862463). This variant disrupts the E2-like fold (ELF) domain of the FANCL protein, which is required for its interaction with the FANCB-FAAP100 complex as well as for non-covalent binding to ubiquitin (PMID: 26149689, 27986371). While functional studies have not been performed to directly test the effect of this variant on FANCL protein function, this suggests that disruption of this region of the protein is causative of disease. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T;T;.;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-1.3	N;N;N;N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;.;.
Polyphen		0.17	B;B;B;B;.
Vest4		0.62
MutPred		1.0		Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);Loss of catalytic residue at M1 (P = 0.0394);
MVP		0.57
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs761291501; hg19: chr2-58468447;