Genetic Variant FANCL:c.-39A>T (chr2-58241352-T-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000449070.6(FANCL):c.-39A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,441,740 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FANCL
ENST00000449070.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.969

Publications

0 publications found

Variant links:

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

FANCL links:

ENSG00000273063 (HGNC:):

ENSG00000273063 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FANCL	NM_018062.4	MANE Select	c.-39A>T	upstream_gene	N/A	NP_060532.2
FANCL	NM_001438889.1		c.-39A>T	upstream_gene	N/A	NP_001425818.1
FANCL	NM_001410792.1		c.-39A>T	upstream_gene	N/A	NP_001397721.1	A0A8Q3SIK5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
FANCL	ENST00000449070.6	TSL:1	c.-39A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000401280.2	C9JZA9
FANCL	ENST00000449070.6	TSL:1	c.-39A>T	5_prime_UTR	Exon 1 of 11	ENSP00000401280.2	C9JZA9
FANCL	ENST00000696326.1		c.-39A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000512562.1	A0A8Q3SIK5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441740

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717978

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33032

American (AMR)

AF:

0.00

AC:

AN:

44014

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25918

East Asian (EAS)

AF:

0.00

AC:

AN:

39440

South Asian (SAS)

AF:

0.00

AC:

AN:

85478

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51506

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

9.12e-7

AC:

AN:

1096996

Other (OTH)

AF:

0.00

AC:

AN:

59740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

0.92

(source)

DANN

Benign

0.57

PhyloP100

-0.97

PromoterAI

-0.00080

Neutral

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over