Genetic Variant FUCA2:p.Arg254Gln (chr6-143502557-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032020.5(FUCA2):c.761G>A(p.Arg254Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,612,142 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

FUCA2
NM_032020.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.89

Variant links:

Genes affected

FUCA2 (HGNC:4008): (alpha-L-fucosidase 2) This gene encodes a plasma alpha-L-fucosidase, which represents 10-20% of the total cellular fucosidase activity. The protein is a member of the glycosyl hydrolase 29 family, and catalyzes the hydrolysis of the alpha-1,6-linked fucose joined to the reducing-end N-acetylglucosamine of the carbohydrate moieties of glycoproteins. This enzyme is essential for Helicobacter pylori adhesion to human gastric cancer cells. [provided by RefSeq, Aug 2010]

FUCA2 links:

VDAC1P8 (HGNC:37483): (voltage dependent anion channel 1 pseudogene 8)

VDAC1P8 links:

ENSG00000278206 (HGNC:):

ENSG00000278206 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUCA2	NM_032020.5 link	c.761G>A	p.Arg254Gln	missense_variant	Exon 4 of 7	ENST00000002165.11	NP_114409.2	Q9BTY2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUCA2	ENST00000002165.11 link	c.761G>A	p.Arg254Gln	missense_variant	Exon 4 of 7	1	NM_032020.5	ENSP00000002165.5		Q9BTY2-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000588

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.0000401

AC:

AN:

249484

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000878

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000333

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000442

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460034

Hom.:

Cov.:

AF XY:

0.0000441

AC XY:

AN XY:

726194

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000113

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000958

Bravo

AF:

0.000110

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 10, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.761G>A (p.R254Q) alteration is located in exon 4 (coding exon 4) of the FUCA2 gene. This alteration results from a G to A substitution at nucleotide position 761, causing the arginine (R) at amino acid position 254 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.056

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.064

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.019

MetaRNN

Uncertain

0.49

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PrimateAI

Benign

0.42

PROVEAN

Benign

-1.9

REVEL

Benign

0.15

Sift

Uncertain

0.013

Sift4G

Uncertain

0.014

Polyphen

0.95

Vest4

0.32

MutPred

0.62

Loss of methylation at R254 (P = 0.0332);

MVP

0.61

MPC

0.57

ClinPred

0.35

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over