dbSNP rs114490852: FUCA1:p.Thr383Ile (chr1-23848661-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000147.5(FUCA1):c.1148C>T(p.Thr383Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00243 in 1,614,104 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T383T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0088 ( 16 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 24 hom. )

Consequence

FUCA1
NM_000147.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.603

Publications

5 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), G2P, Ambry Genetics, ClinGen, Orphanet, Genomics England PanelApp

FUCA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.003978491).

BP6

Variant 1-23848661-G-A is Benign according to our data. Variant chr1-23848661-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 296885.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00883 (1345/152298) while in subpopulation AFR AF = 0.0271 (1128/41554). AF 95% confidence interval is 0.0258. There are 16 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000147.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUCA1	NM_000147.5	MANE Select	c.1148C>T	p.Thr383Ile	missense	Exon 6 of 8	NP_000138.2	P04066
FUCA1	NR_174379.1		n.1326C>T		non_coding_transcript_exon	Exon 6 of 8
FUCA1	NR_174380.1		n.1375C>T		non_coding_transcript_exon	Exon 7 of 9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FUCA1	ENST00000374479.4	TSL:1 MANE Select	c.1148C>T	p.Thr383Ile	missense	Exon 6 of 8	ENSP00000363603.3	P04066
FUCA1	ENST00000965619.1		c.1148C>T	p.Thr383Ile	missense	Exon 6 of 8	ENSP00000635678.1
FUCA1	ENST00000881205.1		c.947C>T	p.Thr316Ile	missense	Exon 5 of 7	ENSP00000551264.1

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1339

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00661

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.00118

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00332

AC:

836

AN:

251454

AF XY:

0.00266

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.00489

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00131

Gnomad OTH exome

AF:

0.00505

GnomAD4 exome

AF:

0.00176

AC:

2573

AN:

1461806

Hom.:

Cov.:

AF XY:

0.00165

AC XY:

1197

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.0292

AC:

979

AN:

33474

American (AMR)

AF:

0.00579

AC:

259

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00867

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000878

AC:

976

AN:

1111942

Other (OTH)

AF:

0.00392

AC:

237

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

132

265

397

530

662

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.00883

AC:

1345

AN:

152298

Hom.:

Cov.:

AF XY:

0.00826

AC XY:

615

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0271

AC:

1128

AN:

41554

American (AMR)

AF:

0.00660

AC:

101

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00118

AC:

AN:

68030

Other (OTH)

AF:

0.0104

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

190

254

317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00407

Hom.:

Bravo

AF:

0.0107

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0293

AC:

129

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.00366

AC:

445

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.00120

EpiControl

AF:

0.00207

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Fucosidosis (2)

FUCA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.72

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.56

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0040

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

PhyloP100

0.60

PrimateAI

Benign

0.26

PROVEAN

Pathogenic

-5.1

REVEL

Benign

0.12

Sift

Uncertain

0.011

Sift4G

Uncertain

0.024

Polyphen

0.0010

Vest4

0.22

MVP

0.48

MPC

0.35

ClinPred

0.035

GERP RS

1.4

Varity_R

0.15

gMVP

0.66

Mutation Taster

=89/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over