rs761291501

Variant names:

• chr2-58241312-A-C
• rs761291501
• NM_018062.4:c.2T>G

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Pathogenic. The variant received 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
• 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, Laboratory for Molecular Medicine, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000273063 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 24 pathogenic variants. Next in-frame start position is after 74 codons. Genomic position: 58226781. Lost 0.195 part of the original CDS.
• PS1: Another start lost variant in NM_018062.4 (FANCL) was described as [Likely_pathogenic] in ClinVar
• 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 VariationId is 862463.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2T>G	p.Met1?	start_lost	Exon 1 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.2T>G	p.Met1?	start_lost	Exon 1 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.2T>G	p.Met1?	start_lost	Exon 1 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.2T>G	p.Met1?	start_lost	Exon 1 of 14	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000403295.8	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 13	ENSP00000386097.3	B5MC31
	FANCL	ENST00000449070.6	TSL:1	c.2T>G	p.Met1?	start_lost	Exon 1 of 11	ENSP00000401280.2	C9JZA9

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111984

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.0030
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.92	T
PhyloP100		1.1
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.24
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		0.17	B
Vest4		0.62
MutPred		1.0		Loss of catalytic residue at M1 (P = 0.0394)
MVP		0.57
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		-0.74	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.68
Mutation Taster		=7/193	disease causing (ClinVar)

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: rs761291501; hg19: chr2-58468447;