chr2-58226795-A-G

Variant names:

• chr2-58226795-A-G
• rs79588315
• NM_018062.4:c.217-11T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_018062.4(FANCL):​c.217-11T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0837 in 1,605,374 control chromosomes in the GnomAD database, including 6,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (408 hom., cov: 32)
  • Exomes 𝑓: 0.086 (5833 hom.)
• Consequence: FANCL NM_018062.4 intron
• Scores: Splicing: ADA: 0.7185
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.73
• Publications: 9 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 2-58226795-A-G is Benign according to our data. Variant chr2-58226795-A-G is described in ClinVar as Benign. ClinVar VariationId is 257493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

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.217-11T>C		intron	N/A	NP_060532.2
	FANCL	NM_001438889.1		c.217-11T>C		intron	N/A	NP_001425818.1
	FANCL	NM_001410792.1		c.217-11T>C		intron	N/A	NP_001397721.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.217-11T>C		intron	N/A	ENSP00000233741.5
	FANCL	ENST00000403295.8	TSL:1	c.217-11T>C		intron	N/A	ENSP00000386097.3
	FANCL	ENST00000449070.6	TSL:1	c.97-4753T>C		intron	N/A	ENSP00000401280.2

Frequencies

GnomAD3 genomes AF: 0.0646 AC: 9826 AN: 152106 Hom.: 408 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0625

Gnomad ASJ AF: 0.0717

Gnomad EAS AF: 0.0212

Gnomad SAS AF: 0.0381

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.0755

GnomAD2 exomes AF: 0.0678 AC: 16983 AN: 250540 AF XY: 0.0691

Gnomad AFR exome AF: 0.0281

Gnomad AMR exome AF: 0.0481

Gnomad ASJ exome AF: 0.0700

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0960

Gnomad OTH exome AF: 0.0786

GnomAD4 exome AF: 0.0857 AC: 124516 AN: 1453148 Hom.: 5833 Cov.: 30 AF XY: 0.0847 AC XY: 61245 AN XY: 723394

African (AFR) AF: 0.0286 AC: 953 AN: 33356

American (AMR) AF: 0.0508 AC: 2269 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 1855 AN: 26080

East Asian (EAS) AF: 0.0275 AC: 1086 AN: 39556

South Asian (SAS) AF: 0.0422 AC: 3629 AN: 85928

European-Finnish (FIN) AF: 0.0642 AC: 3430 AN: 53400

Middle Eastern (MID) AF: 0.0633 AC: 363 AN: 5738

European-Non Finnish (NFE) AF: 0.0958 AC: 105757 AN: 1104286

Other (OTH) AF: 0.0860 AC: 5174 AN: 60128

GnomAD4 genome AF: 0.0645 AC: 9824 AN: 152226 Hom.: 408 Cov.: 32 AF XY: 0.0628 AC XY: 4672 AN XY: 74434

African (AFR) AF: 0.0297 AC: 1234 AN: 41544

American (AMR) AF: 0.0625 AC: 955 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0717 AC: 249 AN: 3472

East Asian (EAS) AF: 0.0212 AC: 110 AN: 5184

South Asian (SAS) AF: 0.0379 AC: 183 AN: 4828

European-Finnish (FIN) AF: 0.0587 AC: 622 AN: 10600

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0921 AC: 6260 AN: 67988

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0738 Hom.: 186

Bravo AF: 0.0623

Asia WGS AF: 0.0240 AC: 84 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Fanconi anemia complementation group L (4)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: 48
DS_AL_spliceai		0.37		Position offset: -11

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

Other links and lift over

dbSNP: rs79588315; hg19: chr2-58453930;