rs143691289

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000147.5(FUCA1):c.402G>C(p.Leu134Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00407 in 1,614,196 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L134V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 22 hom. )

Consequence

FUCA1
NM_000147.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.44

Publications

8 publications found

Variant links:

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

FUCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000147.5

BP4

Computational evidence support a benign effect (MetaRNN=0.017388493).

BP6

Variant 1-23865613-C-G is Benign according to our data. Variant chr1-23865613-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0036 (548/152314) while in subpopulation AMR AF = 0.00392 (60/15298). AF 95% confidence interval is 0.00352. There are 0 homozygotes in GnomAd4. There are 304 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FUCA1	NM_000147.5 link	c.402G>C	p.Leu134Phe	missense_variant	Exon 2 of 8	ENST00000374479.4	NP_000138.2	P04066

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FUCA1	ENST00000374479.4 link	c.402G>C	p.Leu134Phe	missense_variant	Exon 2 of 8	1	NM_000147.5	ENSP00000363603.3		P04066

Frequencies

GnomAD3 genomes

AF:

0.00360

AC:

548

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.0133

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00391

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.00334

AC:

839

AN:

251484

AF XY:

0.00325

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00179

Gnomad ASJ exome

AF:

0.0107

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00878

Gnomad NFE exome

AF:

0.00379

Gnomad OTH exome

AF:

0.00472

GnomAD4 exome

AF:

0.00412

AC:

6017

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00402

AC XY:

2925

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

33480

American (AMR)

AF:

0.00179

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

305

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000429

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00925

AC:

494

AN:

53414

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00433

AC:

4818

AN:

1112010

Other (OTH)

AF:

0.00411

AC:

248

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

349

698

1046

1395

1744

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

198

396

594

792

990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00360

AC:

548

AN:

152314

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

304

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

41576

American (AMR)

AF:

0.00392

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00104

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0121

AC:

128

AN:

10610

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00391

AC:

266

AN:

68030

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

126

157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00370

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00243

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00395

AC:

ExAC

AF:

0.00297

AC:

361

EpiCase

AF:

0.00354

EpiControl

AF:

0.00528

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fucosidosis

Benign:2

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided

Benign:2

Apr 06, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Apr 18, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

FUCA1-related disorder

Benign:1

Aug 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.020

MetaRNN

Benign

0.017

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.92

PhyloP100

1.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.13

Sift

Benign

0.18

Sift4G

Benign

0.16

Polyphen

0.11

Vest4

0.44

MutPred

0.75

Gain of methylation at K130 (P = 0.09);

MVP

0.61

MPC

0.63

ClinPred

0.038

GERP RS

1.2

Varity_R

0.18

gMVP

0.88

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over