rs13551

Variant names:

• chr1-23854472-T-C
• rs13551
• NM_000147.5:c.857A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000147.5(FUCA1):​c.857A>G​(p.Gln286Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,613,656 control chromosomes in the GnomAD database, including 81,648 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q286Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.27 (6033 hom., cov: 32)
  • Exomes 𝑓: 0.32 (75615 hom.)
• Consequence: FUCA1 NM_000147.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.687
• Publications: 40 publications found

Genes affected

FUCA1 (HGNC:4006): (alpha-L-fucosidase 1) The protein encoded by this gene is a lysosomal enzyme involved in the degradation of fucose-containing glycoproteins and glycolipids. Mutations in this gene are associated with fucosidosis (FUCA1D), which is an autosomal recessive lysosomal storage disease. A pseudogene of this locus is present on chr 2.[provided by RefSeq, Oct 2009]

FUCA1 Gene-Disease associations (from GenCC):

• fucosidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, Genomics England PanelApp, Ambry Genetics, ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.5064092E-4).
• BP6: Variant 1-23854472-T-C is Benign according to our data. Variant chr1-23854472-T-C is described in ClinVar as Benign. ClinVar VariationId is 691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.331 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUCA1	NM_000147.5	c.857A>G	p.Gln286Arg	missense_variant	Exon 5 of 8	ENST00000374479.4	NP_000138.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUCA1	ENST00000374479.4	c.857A>G	p.Gln286Arg	missense_variant	Exon 5 of 8	1	NM_000147.5	ENSP00000363603.3

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40805 AN: 152038 Hom.: 6032 Cov.: 32

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.400

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.335

Gnomad OTH AF: 0.288

GnomAD2 exomes AF: 0.279 AC: 70217 AN: 251490 AF XY: 0.278

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.204

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.265

Gnomad FIN exome AF: 0.384

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.296

GnomAD4 exome AF: 0.315 AC: 460378 AN: 1461500 Hom.: 75615 Cov.: 36 AF XY: 0.311 AC XY: 226103 AN XY: 727112

African (AFR) AF: 0.136 AC: 4553 AN: 33478

American (AMR) AF: 0.207 AC: 9274 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 7975 AN: 26136

East Asian (EAS) AF: 0.253 AC: 10056 AN: 39698

South Asian (SAS) AF: 0.155 AC: 13377 AN: 86256

European-Finnish (FIN) AF: 0.393 AC: 20977 AN: 53420

Middle Eastern (MID) AF: 0.235 AC: 1357 AN: 5768

European-Non Finnish (NFE) AF: 0.337 AC: 374375 AN: 1111646

Other (OTH) AF: 0.305 AC: 18434 AN: 60374

GnomAD4 genome AF: 0.268 AC: 40816 AN: 152156 Hom.: 6033 Cov.: 32 AF XY: 0.266 AC XY: 19773 AN XY: 74378

African (AFR) AF: 0.145 AC: 6011 AN: 41538

American (AMR) AF: 0.239 AC: 3647 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3470

East Asian (EAS) AF: 0.264 AC: 1370 AN: 5182

South Asian (SAS) AF: 0.148 AC: 714 AN: 4832

European-Finnish (FIN) AF: 0.400 AC: 4217 AN: 10554

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.335 AC: 22783 AN: 67988

Other (OTH) AF: 0.286 AC: 604 AN: 2112

Alfa AF: 0.304 Hom.: 17095

Bravo AF: 0.254

TwinsUK AF: 0.346 AC: 1283

ALSPAC AF: 0.331 AC: 1274

ESP6500AA AF: 0.146 AC: 643

ESP6500EA AF: 0.331 AC: 2845

ExAC AF: 0.279 AC: 33884

Asia WGS AF: 0.187 AC: 652 AN: 3478

EpiCase AF: 0.325

EpiControl AF: 0.315

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

May 02, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The FUCA1 c.857A>G (p.Gln286Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant, however experimental findings confirmed, that Q289R retained its functional activity. This variant was found in 33884/121394 control chromosomes (5299 homozygotes) at a frequency of 0.2791242, which is approximately 250 times the estimated maximal expected allele frequency of a pathogenic FUCA1 variant (0.001118), strong evidence that this variant is a benign polymorphism. The variant has been reported in the literature in affected individuals who also carry known pathogenic FUCA1 variants, and has been shown to be present in the homozygous state in numerous unaffected relatives, indicating the variant does not segregate with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. Taken together, this variant is classified as benign. -

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fucosidosis Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

FU1/FU2 POLYMORPHISM Benign:1

Aug 01, 1994

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.033	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.00045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.24	N
PhyloP100		0.69
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.42	N
REVEL	Benign	0.057
Sift	Benign	0.038	D
Sift4G	Benign	0.074	T
Polyphen		0.0010	B
Vest4		0.014
MPC		0.35
ClinPred		0.0057	T
GERP RS		3.6
Varity_R		0.093
gMVP		0.58
Mutation Taster		=99/1	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: rs13551; hg19: chr1-24180962; COSMIC: COSV65698861;