16-70463727-G-A

Variant names:

• chr16-70463727-G-A
• rs200603725
• NM_145059.3:c.187G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_145059.3(FCSK):​c.187G>A​(p.Ala63Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000496 in 1,612,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: FCSK NM_145059.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 8.73
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32613733).

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.187G>A	p.Ala63Thr	missense	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.187G>A	p.Ala63Thr	missense	Exon 3 of 24	ENSP00000288078.6	Q8N0W3-1
	FCSK	ENST00000378912.6	TSL:2	c.187G>A	p.Ala63Thr	missense	Exon 3 of 24	ENSP00000368192.2	Q8N0W3-2
	FCSK	ENST00000864954.1		c.187G>A	p.Ala63Thr	missense	Exon 3 of 24	ENSP00000535013.1

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000222 AC: 55 AN: 247902 AF XY: 0.000215

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000464

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000525 AC: 767 AN: 1460286 Hom.: 0 Cov.: 31 AF XY: 0.000538 AC XY: 391 AN XY: 726492

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000671 AC: 3 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5034

European-Non Finnish (NFE) AF: 0.000659 AC: 733 AN: 1111930

Other (OTH) AF: 0.000481 AC: 29 AN: 60292

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74324

African (AFR) AF: 0.0000483 AC: 2 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68028

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

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000204

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000713 AC: 6

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.17
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.058	T
Polyphen		1.0	D
Vest4		0.83
MVP		0.76
MPC		0.37
ClinPred		0.27	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.66
Mutation Taster		=20/80	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: rs200603725; hg19: chr16-70497630;