rs13551

Positions:

• chr1-23854472-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000374479.4(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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6033 hom., cov: 32)
  • Exomes 𝑓: 0.32 (75615 hom.)
• Consequence: FUCA1 ENST00000374479.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.687

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
FUCA1	NM_000147.5	c.857A>G	p.Gln286Arg	missense_variant	5/8	ENST00000374479.4	NP_000138.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FUCA1	ENST00000374479.4	c.857A>G	p.Gln286Arg	missense_variant	5/8	1	NM_000147.5	ENSP00000363603	P1

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

GnomAD3 exomes AF: 0.279 AC: 70217 AN: 251490 Hom.: 10693 AF XY: 0.278 AC XY: 37816 AN XY: 135922

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 SAS exome AF: 0.152

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

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.305

Gnomad4 EAS exome AF: 0.253

Gnomad4 SAS exome AF: 0.155

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.337

Gnomad4 OTH exome AF: 0.305

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

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.239

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.264

Gnomad4 SAS AF: 0.148

Gnomad4 FIN AF: 0.400

Gnomad4 NFE AF: 0.335

Gnomad4 OTH AF: 0.286

Alfa AF: 0.313 Hom.: 12852

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2017	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -

Fucosidosis Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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

Benign, no assertion criteria provided

literature only

OMIM

Aug 01, 1994

- -

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
MutationTaster	Benign	1.0	P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs13551; hg19: chr1-24180962; COSMIC: COSV65698861;