rs139801716

Variant names:

• chr2-58163454-A-C
• rs139801716
• NM_018062.4:c.755T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018062.4(FANCL):​c.755T>G​(p.Phe252Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,610,222 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F252L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (45 hom.)
• Consequence: FANCL NM_018062.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.199
• Publications: 7 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]

VRK2 (HGNC:12719): (VRK serine/threonine kinase 2) This gene encodes a member of the vaccinia-related kinase (VRK) family of serine/threonine protein kinases. The encoded protein acts as an effector of signaling pathways that regulate apoptosis and tumor cell growth. Variants in this gene have been associated with schizophrenia. Alternative splicing results in multiple transcript variants that differ in their subcellular localization and biological activity. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059069097).
• BP6: Variant 2-58163454-A-C is Benign according to our data. Variant chr2-58163454-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220759.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000914 (139/152060) while in subpopulation SAS AF = 0.0277 (133/4810). AF 95% confidence interval is 0.0238. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 45 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	NM_018062.4	MANE Select	c.755T>G	p.Phe252Cys	missense	Exon 9 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.800T>G	p.Phe267Cys	missense	Exon 10 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.815T>G	p.Phe272Cys	missense	Exon 10 of 15	NP_001397721.1	A0A8Q3SIK5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.755T>G	p.Phe252Cys	missense	Exon 9 of 14	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000449070.6	TSL:1	c.578T>G	p.Phe193Cys	missense	Exon 6 of 11	ENSP00000401280.2	C9JZA9
	FANCL	ENST00000403295.8	TSL:1	c.692-380T>G		intron	N/A	ENSP00000386097.3	B5MC31

Frequencies

GnomAD3 genomes AF: 0.000915 AC: 139 AN: 151942 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0276

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.00301 AC: 755 AN: 250538 AF XY: 0.00382

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00147 AC: 2144 AN: 1458162 Hom.: 45 Cov.: 29 AF XY: 0.00210 AC XY: 1525 AN XY: 725612

African (AFR) AF: 0.0000599 AC: 2 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44670

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39624

South Asian (SAS) AF: 0.0229 AC: 1974 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.0000577 AC: 64 AN: 1108860

Other (OTH) AF: 0.00164 AC: 99 AN: 60260

GnomAD4 genome AF: 0.000914 AC: 139 AN: 152060 Hom.: 1 Cov.: 32 AF XY: 0.00130 AC XY: 97 AN XY: 74348

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.000196 AC: 3 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0277 AC: 133 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67824

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000336 Hom.: 3

Bravo AF: 0.000196

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00343 AC: 416

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia complementation group L (2)
-	-	1	FANCL-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.87	N
PhyloP100		0.20
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.17
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.33
MVP		0.22
MPC		0.0088
ClinPred		0.014	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.41
Mutation Taster		=95/5	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: rs139801716; hg19: chr2-58390589; COSMIC: COSV52073581; COSMIC: COSV52073581;