rs144015992

Positions:

chr3-155829719-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_004733.4(SLC33A1):c.1451A>C(p.Asn484Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00297 in 1,613,974 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 6 hom. )

Consequence

SLC33A1
NM_004733.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.878

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067625046).

BP6

Variant 3-155829719-T-G is Benign according to our data. Variant chr3-155829719-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 343875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-155829719-T-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC33A1	NM_004733.4 linkuse as main transcript	c.1451A>C	p.Asn484Thr	missense_variant	5/6	ENST00000643144.2	NP_004724.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC33A1	ENST00000643144.2 linkuse as main transcript	c.1451A>C	p.Asn484Thr	missense_variant	5/6		NM_004733.4	ENSP00000496241	P1

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

278

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000797

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00298

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.00175

AC:

440

AN:

251474

Hom.:

AF XY:

0.00176

AC XY:

239

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00105

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00302

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00309

AC:

4510

AN:

1461754

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2175

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.00107

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.00373

Gnomad4 OTH exome

AF:

0.00247

GnomAD4 genome

AF:

0.00183

AC:

278

AN:

152220

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000795

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.000773

Gnomad4 SAS

AF:

0.000624

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.00298

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.00229

Hom.:

Bravo

AF:

0.00193

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00165

AC:

200

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2021	This variant is associated with the following publications: (PMID: 31227335) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	SLC33A1: BP4, BS1 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 06, 2021

- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 04, 2024

- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 03, 2020

- -

Hereditary spastic paraplegia 42;C4751114:Huppke-Brendel syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 08, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.066

T;T;T;.;.

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.69

.;.;T;T;T

M_CAP

Benign

0.0077

MetaRNN

Benign

0.0068

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.080

N;N;N;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.43

N;.;N;.;N

REVEL

Benign

0.10

Sift

Benign

0.89

T;.;T;.;T

Sift4G

Benign

0.77

T;.;T;.;T

Polyphen

0.0020

B;B;B;.;.

Vest4

0.20

MVP

0.61

MPC

0.39

ClinPred

0.0028

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.039

gMVP

0.47

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over