2-58163497-T-G

Variant names:

• chr2-58163497-T-G
• rs776189946
• NM_018062.4:c.712A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_018062.4(FANCL):​c.712A>C​(p.Ile238Leu) variant causes a missense 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I238V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FANCL NM_018062.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.645
• Publications: 2 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2925163).

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.712A>C	p.Ile238Leu	missense	Exon 9 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.757A>C	p.Ile253Leu	missense	Exon 10 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.772A>C	p.Ile258Leu	missense	Exon 10 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.712A>C	p.Ile238Leu	missense	Exon 9 of 14	ENSP00000233741.5
	FANCL	ENST00000449070.6	TSL:1	c.535A>C	p.Ile179Leu	missense	Exon 6 of 11	ENSP00000401280.2
	FANCL	ENST00000403295.8	TSL:1	c.692-423A>C		intron	N/A	ENSP00000386097.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250176 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.097	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.65
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.26
Sift	Benign	0.22	T
Sift4G	Benign	0.28	T
Polyphen		0.097	B
Vest4		0.44
MutPred		0.68		Loss of glycosylation at S235 (P = 0.084)
MVP		0.30
MPC		0.013
ClinPred		0.50	D
GERP RS		5.7
Varity_R		0.46
gMVP		0.45
Mutation Taster		=77/23	polymorphism

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: rs776189946; hg19: chr2-58390632;