rs753105795

Variant names:

• chr2-58229819-G-A
• rs753105795
• NM_018062.4:c.211C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-58229819-G-A
• chr2-58229819-G-C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018062.4(FANCL):​c.211C>T​(p.Gln71*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q71Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCL NM_018062.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.23
• Publications: 0 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-58229819-G-A is Pathogenic according to our data. Variant chr2-58229819-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 526347.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	NM_018062.4	MANE Select	c.211C>T	p.Gln71*	stop_gained	Exon 3 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.211C>T	p.Gln71*	stop_gained	Exon 3 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.211C>T	p.Gln71*	stop_gained	Exon 3 of 15	NP_001397721.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.211C>T	p.Gln71*	stop_gained	Exon 3 of 14	ENSP00000233741.5
	FANCL	ENST00000403295.8	TSL:1	c.211C>T	p.Gln71*	stop_gained	Exon 3 of 13	ENSP00000386097.3
	FANCL	ENST00000449070.6	TSL:1	c.97-7777C>T		intron	N/A	ENSP00000401280.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454342 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724090

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105432

Other (OTH) AF: 0.00 AC: 0 AN: 60086

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

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	Pathogenic	0.49
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		1.2
Vest4		0.92
ClinPred		1.0	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=0/200	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: rs753105795; hg19: chr2-58456954;