rs76440173

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2

The NM_004733.4(SLC33A1):c.1525G>A(p.Gly509Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00347 in 1,607,140 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 15 hom. )

Consequence

SLC33A1
NM_004733.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 6.02

Publications

5 publications found

Variant links:

Genes affected

SLC33A1 (HGNC:95): (solute carrier family 33 member 1) The protein encoded by this gene is required for the formation of O-acetylated (Ac) gangliosides. The encoded protein is predicted to contain 6 to 10 transmembrane domains, and a leucine zipper motif in transmembrane domain III. Defects in this gene have been reported to cause spastic paraplegia autosomal dominant type 42 (SPG42) in one Chinese family, but not in similar patients of European descent. Two transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2010]

SLC33A1 Gene-Disease associations (from GenCC):

Huppke-Brendel syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
hereditary spastic paraplegia 42
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Illumina, Orphanet

SLC33A1 links:

ENSG00000284952 (HGNC:):

ENSG00000284952 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, M_CAP, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.1720002).

BP6

Variant 3-155828335-C-T is Benign according to our data. Variant chr3-155828335-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 343874.

BS2

High Homozygotes in GnomAdExome4 at 15 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC33A1	NM_004733.4 link	c.1525G>A	p.Gly509Ser	missense_variant	Exon 6 of 6	ENST00000643144.2	NP_004724.1	O00400

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC33A1	ENST00000643144.2 link	c.1525G>A	p.Gly509Ser	missense_variant	Exon 6 of 6	NM_004733.4	ENSP00000496241.1	O00400
ENSG00000284952	ENST00000643876.1 link	n.*847G>A		non_coding_transcript_exon_variant	Exon 6 of 10		ENSP00000495323.1	A0A2R8Y6H1
ENSG00000284952	ENST00000643876.1 link	n.*847G>A		3_prime_UTR_variant	Exon 6 of 10		ENSP00000495323.1	A0A2R8Y6H1

Frequencies

GnomAD3 genomes

AF:

0.00252

AC:

383

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000567

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00470

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.00180

AC:

453

AN:

251204

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00102

Gnomad NFE exome

AF:

0.00363

Gnomad OTH exome

AF:

0.000980

GnomAD4 exome

AF:

0.00357

AC:

5196

AN:

1454908

Hom.:

Cov.:

AF XY:

0.00346

AC XY:

2509

AN XY:

724304

show subpopulations

African (AFR)

AF:

0.000900

AC:

AN:

33334

American (AMR)

AF:

0.000112

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39616

South Asian (SAS)

AF:

0.00

AC:

AN:

86130

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00452

AC:

5001

AN:

1105728

Other (OTH)

AF:

0.00170

AC:

102

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

238

476

715

953

1191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

204

408

612

816

1020

<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:

0.00252

AC:

383

AN:

152232

Hom.:

Cov.:

AF XY:

0.00251

AC XY:

187

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41550

American (AMR)

AF:

0.0000654

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000567

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00471

AC:

320

AN:

68012

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

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:

0.00318

Hom.:

Bravo

AF:

0.00218

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00314

AC:

ExAC

AF:

0.00161

AC:

196

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Sep 02, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 24583203) -

Dec 29, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SLC33A1: BS1, BS2 -

not specified

Benign:1

May 29, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia 42

Benign:1

Oct 31, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2. -

Hereditary spastic paraplegia

Benign:1

Mar 16, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

D;D;D;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

.;.;D;D;D

M_CAP

Benign

0.062

MetaRNN

Benign

0.17

T;T;T;T;T

MetaSVM

Uncertain

0.32

MutationAssessor

Pathogenic

3.8

H;H;H;.;.

PhyloP100

6.0

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.4

D;.;D;.;D

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.;D;.;D

Sift4G

Uncertain

0.0060

D;.;D;.;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.88

MVP

0.92

MPC

1.2

ClinPred

0.74

GERP RS

4.9

Varity_R

0.92

gMVP

0.95

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over