ENST00000449070.6:c.-39A>C

Variant names:

• chr2-58241352-T-G
• rs41281511
• ENST00000449070.6:c.-39A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000449070.6(FANCL):​c.-39A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,594,112 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: FANCL ENST00000449070.6 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:1
• Conservation: PhyloP100: -0.969
• Publications: 3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00103 (157/152384) while in subpopulation NFE AF = 0.00184 (125/68036). AF 95% confidence interval is 0.00158. There are 0 homozygotes in GnomAd4. There are 73 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000449070.6. 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.-39A>C		upstream_gene	N/A	NP_060532.2
	FANCL	NM_001438889.1		c.-39A>C		upstream_gene	N/A	NP_001425818.1
	FANCL	NM_001410792.1		c.-39A>C		upstream_gene	N/A	NP_001397721.1	A0A8Q3SIK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000449070.6	TSL:1	c.-39A>C		5_prime_UTR	Exon 1 of 11	ENSP00000401280.2	C9JZA9
	FANCL	ENST00000696326.1		c.-39A>C		5_prime_UTR	Exon 1 of 15	ENSP00000512562.1	A0A8Q3SIK5
	FANCL	ENST00000402135.8	TSL:2	c.-39A>C		5_prime_UTR	Exon 1 of 14	ENSP00000385021.3	Q9NW38-2

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152266 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000846 AC: 199 AN: 235150 AF XY: 0.000814

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.000509

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000574

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.00192 AC: 2761 AN: 1441728 Hom.: 6 Cov.: 26 AF XY: 0.00180 AC XY: 1293 AN XY: 717974

African (AFR) AF: 0.000878 AC: 29 AN: 33032

American (AMR) AF: 0.000477 AC: 21 AN: 44014

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25918

East Asian (EAS) AF: 0.0000761 AC: 3 AN: 39440

South Asian (SAS) AF: 0.00 AC: 0 AN: 85478

European-Finnish (FIN) AF: 0.000136 AC: 7 AN: 51506

Middle Eastern (MID) AF: 0.000178 AC: 1 AN: 5616

European-Non Finnish (NFE) AF: 0.00239 AC: 2624 AN: 1096986

Other (OTH) AF: 0.00126 AC: 75 AN: 59738

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152384 Hom.: 0 Cov.: 33 AF XY: 0.000979 AC XY: 73 AN XY: 74528

African (AFR) AF: 0.000577 AC: 24 AN: 41600

American (AMR) AF: 0.000392 AC: 6 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68036

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.00111

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	FANCL-related disorder (1)
-	1	-	Fanconi anemia complementation group L (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.0
DANN	Benign	0.43
PhyloP100		-0.97
PromoterAI		0.16	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs41281511; hg19: chr2-58468487;