rs11539575

Variant names:

• chr2-58160123-A-G
• rs11539575
• NM_018062.4:c.1077T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001438889.1(FANCL):​c.1122T>C​(p.Cys374Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,612,658 control chromosomes in the GnomAD database, including 329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (24 hom., cov: 32)
  • Exomes 𝑓: 0.019 (305 hom.)
• Consequence: FANCL NM_001438889.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.49
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 2-58160123-A-G is Benign according to our data. Variant chr2-58160123-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2069/152184) while in subpopulation NFE AF = 0.0209 (1419/67924). AF 95% confidence interval is 0.02. There are 24 homozygotes in GnomAd4. There are 965 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001438889.1. 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.1077T>C	p.Cys359Cys	synonymous	Exon 13 of 14	NP_060532.2
	FANCL	NM_001438889.1		c.1122T>C	p.Cys374Cys	synonymous	Exon 14 of 14	NP_001425818.1
	FANCL	NM_001410792.1		c.1137T>C	p.Cys379Cys	synonymous	Exon 14 of 15	NP_001397721.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCL	ENST00000233741.9	TSL:1 MANE Select	c.1077T>C	p.Cys359Cys	synonymous	Exon 13 of 14	ENSP00000233741.5
	FANCL	ENST00000403295.8	TSL:1	c.993T>C	p.Cys331Cys	synonymous	Exon 12 of 13	ENSP00000386097.3
	FANCL	ENST00000449070.6	TSL:1	c.900T>C	p.Cys300Cys	synonymous	Exon 10 of 11	ENSP00000401280.2

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2067 AN: 152066 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00434

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0138

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00890

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0209

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.0135 AC: 3374 AN: 250798 AF XY: 0.0137

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00862

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00878

Gnomad NFE exome AF: 0.0207

Gnomad OTH exome AF: 0.0149

GnomAD4 exome AF: 0.0186 AC: 27213 AN: 1460474 Hom.: 305 Cov.: 31 AF XY: 0.0182 AC XY: 13232 AN XY: 726570

African (AFR) AF: 0.00356 AC: 119 AN: 33446

American (AMR) AF: 0.00917 AC: 410 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0149 AC: 389 AN: 26088

East Asian (EAS) AF: 0.0000506 AC: 2 AN: 39564

South Asian (SAS) AF: 0.00799 AC: 689 AN: 86234

European-Finnish (FIN) AF: 0.00959 AC: 512 AN: 53412

Middle Eastern (MID) AF: 0.0278 AC: 160 AN: 5750

European-Non Finnish (NFE) AF: 0.0216 AC: 23941 AN: 1110932

Other (OTH) AF: 0.0164 AC: 991 AN: 60330

GnomAD4 genome AF: 0.0136 AC: 2069 AN: 152184 Hom.: 24 Cov.: 32 AF XY: 0.0130 AC XY: 965 AN XY: 74426

African (AFR) AF: 0.00433 AC: 180 AN: 41566

American (AMR) AF: 0.0138 AC: 210 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4826

European-Finnish (FIN) AF: 0.0107 AC: 114 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0209 AC: 1419 AN: 67924

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0187 Hom.: 52

Bravo AF: 0.0132

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0219

EpiControl AF: 0.0216

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia complementation group L (2)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	6.1
DANN	Benign	0.79
PhyloP100		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=83/17	polymorphism (auto)

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: rs11539575; hg19: chr2-58387258; COSMIC: COSV52073891;