rs140088149

Variant names:

• chr2-58161579-A-T
• rs140088149
• NM_018062.4:c.963T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-58161579-A-T
• chr2-58161579-A-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018062.4(FANCL):​c.963T>A​(p.Asp321Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,611,748 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: FANCL NM_018062.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.901
• 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]

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01381591).
• BP6: Variant 2-58161579-A-T is Benign according to our data. Variant chr2-58161579-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241253.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00161 (245/152044) while in subpopulation AFR AF = 0.00568 (236/41538). AF 95% confidence interval is 0.00509. There are 1 homozygotes in GnomAd4. There are 112 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.963T>A	p.Asp321Glu	missense	Exon 12 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.1008T>A	p.Asp336Glu	missense	Exon 13 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.1023T>A	p.Asp341Glu	missense	Exon 13 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.963T>A	p.Asp321Glu	missense	Exon 12 of 14	ENSP00000233741.5	Q9NW38-1
	FANCL	ENST00000403295.8	TSL:1	c.879T>A	p.Asp293Glu	missense	Exon 11 of 13	ENSP00000386097.3	B5MC31
	FANCL	ENST00000449070.6	TSL:1	c.786T>A	p.Asp262Glu	missense	Exon 9 of 11	ENSP00000401280.2	C9JZA9

Frequencies

GnomAD3 genomes AF: 0.00159 AC: 241 AN: 151926 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

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: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000403 AC: 101 AN: 250794 AF XY: 0.000288

Gnomad AFR exome AF: 0.00579

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1459704 Hom.: 1 Cov.: 31 AF XY: 0.000127 AC XY: 92 AN XY: 726218

African (AFR) AF: 0.00587 AC: 196 AN: 33418

American (AMR) AF: 0.000202 AC: 9 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110336

Other (OTH) AF: 0.000398 AC: 24 AN: 60292

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152044 Hom.: 1 Cov.: 32 AF XY: 0.00151 AC XY: 112 AN XY: 74340

African (AFR) AF: 0.00568 AC: 236 AN: 41538

American (AMR) AF: 0.000393 AC: 6 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67842

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.000355 Hom.: 0

Bravo AF: 0.00186

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000519 AC: 63

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		0.90
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.99	D
Vest4		0.57
MutPred		0.77		Gain of helix (P = 0.132)
MVP		0.70
MPC		0.018
ClinPred		0.099	T
GERP RS		2.3
Varity_R		0.72
gMVP		0.57
Mutation Taster		=44/56	disease causing

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: rs140088149; hg19: chr2-58388714; COSMIC: COSV104374379; COSMIC: COSV104374379;