2-58159314-TAACA-T

Variant names:

• chr2-58159314-TAACA-T
• rs748896681
• NM_018062.4:c.*447_*450delTGTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_018062.4(FANCL):​c.*447_*450delTGTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,506,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: FANCL NM_018062.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000367 (497/1354426) while in subpopulation NFE AF = 0.000455 (477/1047398). AF 95% confidence interval is 0.000421. There are 0 homozygotes in GnomAdExome4. There are 223 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCL	NM_018062.4	c.*447_*450delTGTT		3_prime_UTR_variant	Exon 14 of 14	ENST00000233741.9	NP_060532.2
VRK2	NM_006296.7	c.1183-31_1183-28delAAAC		intron_variant	Intron 12 of 12	ENST00000340157.9	NP_006287.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCL	ENST00000233741.9	c.*447_*450delTGTT		3_prime_UTR_variant	Exon 14 of 14	1	NM_018062.4	ENSP00000233741.5
VRK2	ENST00000340157.9	c.1183-31_1183-28delAAAC		intron_variant	Intron 12 of 12	1	NM_006296.7	ENSP00000342381.4

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152056 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000324

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000136 AC: 27 AN: 199086 AF XY: 0.000121

Gnomad AFR exome AF: 0.000135

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: 0.000248

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.000367 AC: 497 AN: 1354426 Hom.: 0 AF XY: 0.000332 AC XY: 223 AN XY: 670998

African (AFR) AF: 0.000101 AC: 3 AN: 29850

American (AMR) AF: 0.0000307 AC: 1 AN: 32548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21582

East Asian (EAS) AF: 0.00 AC: 0 AN: 39016

South Asian (SAS) AF: 0.00 AC: 0 AN: 72340

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50754

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4920

European-Non Finnish (NFE) AF: 0.000455 AC: 477 AN: 1047398

Other (OTH) AF: 0.000286 AC: 16 AN: 56018

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152056 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74268

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15242

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000166

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fanconi anemia Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
BranchPoint Hunter		8.0
Mutation Taster		=99/1	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: rs748896681; hg19: chr2-58386449;