chr16-70463678-C-A

Variant names:

• chr16-70463678-C-A
• rs60470914
• NM_145059.3:c.138C>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_145059.3(FCSK):​c.138C>A​(p.Ala46Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00747 in 1,613,114 control chromosomes in the GnomAD database, including 842 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (443 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (399 hom.)
• Consequence: FCSK NM_145059.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.41
• Publications: 3 publications found

Genes affected

FCSK (HGNC:29500): (fucose kinase) The protein encoded by this gene belongs to the GHMP (galacto-, homoserine, mevalonate and phosphomevalonate) kinase family and catalyzes the phosphorylation of L-fucose to form beta-L-fucose 1-phosphate. This enzyme catalyzes the first step in the utilization of free L-fucose in glycoprotein and glycolipid synthesis. L-fucose may be important in mediating a number of cell-cell interactions such as blood group antigen recognition, inflammation, and metastatis. While several transcript variants may exist for this gene, the full-length nature of only one has been described to date. [provided by RefSeq, Jul 2008]

FCSK Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation with defective fucosylation 2

  Inheritance: AR, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 16-70463678-C-A is Benign according to our data. Variant chr16-70463678-C-A is described in ClinVar as Benign. ClinVar VariationId is 1682342.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.137 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145059.3. 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
	FCSK	NM_145059.3	MANE Select	c.138C>A	p.Ala46Ala	synonymous	Exon 3 of 24	NP_659496.2	Q8N0W3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FCSK	ENST00000288078.11	TSL:1 MANE Select	c.138C>A	p.Ala46Ala	synonymous	Exon 3 of 24	ENSP00000288078.6	Q8N0W3-1
	FCSK	ENST00000378912.6	TSL:2	c.138C>A	p.Ala46Ala	synonymous	Exon 3 of 24	ENSP00000368192.2	Q8N0W3-2
	FCSK	ENST00000864954.1		c.138C>A	p.Ala46Ala	synonymous	Exon 3 of 24	ENSP00000535013.1

Frequencies

GnomAD3 genomes AF: 0.0404 AC: 6140 AN: 151986 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0297

GnomAD2 exomes AF: 0.0101 AC: 2502 AN: 248896 AF XY: 0.00768

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.00658

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00402 AC: 5879 AN: 1461010 Hom.: 399 Cov.: 31 AF XY: 0.00342 AC XY: 2485 AN XY: 726800

African (AFR) AF: 0.144 AC: 4819 AN: 33464

American (AMR) AF: 0.00745 AC: 333 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000359 AC: 31 AN: 86234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

Middle Eastern (MID) AF: 0.00549 AC: 30 AN: 5462

European-Non Finnish (NFE) AF: 0.000104 AC: 116 AN: 1111998

Other (OTH) AF: 0.00911 AC: 550 AN: 60360

GnomAD4 genome AF: 0.0405 AC: 6166 AN: 152104 Hom.: 443 Cov.: 32 AF XY: 0.0392 AC XY: 2913 AN XY: 74384

African (AFR) AF: 0.141 AC: 5823 AN: 41444

American (AMR) AF: 0.0170 AC: 260 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68004

Other (OTH) AF: 0.0294 AC: 62 AN: 2108

Alfa AF: 0.0137 Hom.: 84

Bravo AF: 0.0458

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	FCSK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.076
DANN	Benign	0.48
PhyloP100		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs60470914; hg19: chr16-70497581;