rs149571533

chr3-155853862-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004733.4(SLC33A1):c.136G>A(p.Glu46Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00172 in 1,583,964 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: SLC33A1 NM_004733.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.40

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00451231).
• BP6: Variant 3-155853862-C-T is Benign according to our data. Variant chr3-155853862-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 343883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-155853862-C-T is described in Lovd as [Likely_benign]. Variant chr3-155853862-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC33A1	NM_004733.4	c.136G>A	p.Glu46Lys	missense_variant	1/6	ENST00000643144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC33A1	ENST00000643144.2	c.136G>A	p.Glu46Lys	missense_variant	1/6		NM_004733.4	P1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00232 AC: 525 AN: 226566 Hom.: 3 AF XY: 0.00230 AC XY: 281 AN XY: 122094

Gnomad AFR exome AF: 0.000254

Gnomad AMR exome AF: 0.000131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00149

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.00172

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00171 AC: 2454 AN: 1431662 Hom.: 6 Cov.: 32 AF XY: 0.00172 AC XY: 1223 AN XY: 709190

Gnomad4 AFR exome AF: 0.000155

Gnomad4 AMR exome AF: 0.000245

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.0139

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.00131

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74468

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0142

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00128 Hom.: 1

Bravo AF: 0.000778

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00194 AC: 235

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	SLC33A1: PP2, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 09, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.027	T;T;T;.
Eigen	Benign	-0.087
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0045	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	N;N;N;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.060	N;.;N;.
REVEL	Benign	0.23
Sift	Benign	0.25	T;.;T;.
Sift4G	Benign	0.42	T;.;T;.
Polyphen		0.19	B;B;B;.
Vest4		0.29
MVP		0.81
MPC		1.2
ClinPred		0.037	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.62

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: rs149571533; hg19: chr3-155571651;